Blocking KAT6 to slow aging · Insilico Medicine

Bottom line

What blocking KAT6 would and would not do

Should Insilico run a KAT6 inhibitor as an aging program?

Conditional go in oncology. No-go today for a standalone aging program.

The enzyme is reachable in people. A KAT6 inhibitor has been shown to reduce its target histone mark by more than 70 percent in patients, and one program is in Phase 3. Engagement at a tolerated dose is not in question.

What is missing is any evidence that engaging it helps a person who is not ill. Every human result comes from metastatic breast cancer, and whether the same effect points in the right direction for aging has not been tested.

Translation assessment, page 1

Senescence is the crux

Four of the six reports state that inhibiting KAT6 induces senescence, and none disputes it. In a tumor that is the mechanism of benefit: cells that stop dividing stop growing the cancer. In an aging body, senescent cells are one of the things drugs are built to clear. The same molecular event is the reason to run this program and the reason it could do harm, and no experiment in this pack tells the two apart.

The evidence

Where the evidence stands

Six reports were read for this page. They came from five agents, all on the same day. None of them was written to agree with the others. The headline on each card below is this page’s reading of where that report lands; under it is a sentence quoted from the report itself.

Target evaluationCautionOncology now, aging later: its strongest cancer signals rank in the first twenty-five of a thousand indications, and its best aging indication ranks 42nd.

“Direct evidence for KAT6A/KAT6B inhibition extending lifespan, modulating SASP, or treating specific aging-associated diseases remains absent from the peer-reviewed literature. This is an emerging, largely unexplored frontier.” Section 3, Aging Indication Landscape

Longevity evidence reviewSupportsConvergent evidence across hallmarks, clocks and preclinical biology, with no lifespan experiment behind it.

“While no direct lifespan extension experiment with a KAT6 inhibitor has been published, the convergence of evidence across hallmarks of aging, epigenetic clocks, and preclinical biology provides a compelling rationale for KAT6 inhibition as an anti-aging strategy — particularly in the context of cancer prevention, selective clearance of pre-senescent cells, and epigenetic age modulation.” page 1

Indication prioritizationSupportsParkinson’s disease first, Alzheimer’s disease second, ahead of every cancer.

“Nine diseases show concordant upregulation of both KAT6A and KAT6B, representing the strongest mechanistic rationale for a dual inhibitor.” page 2

Clinical evidence reviewOpposesNo clinical evidence for KAT6 inhibition in aging, and inducing senescence may be the wrong direction.

“There is currently NO clinical evidence for KAT6 inhibition in anti-aging or in any aging-related non-oncology disease.” page 1

Translation assessmentCautionConditional go in oncology; no-go today for a standalone aging program.

“KAT6 is a genuine dual-biology target (cancer and aging share the epigenetic/senescence axis), but it is not yet a dual-purpose clinical asset.” page 1

LongevityClaw assessmentOpposesA KAT6 inhibitor induces senescence rather than clearing it, so a senescence-based aging indication is very unlikely to work.

“A KAT6 inhibitor is very unlikely to help with senescence, because it is a senescence-inducing agent.” Verdict, Probability assessment

What is not in dispute.
The point	Reports	What that agreement is worth
No approved drug exists against KAT6A or KAT6B, and no same-family drug has been approved, failed or withdrawn.	3	No report that addresses this qualifies it. What they disagree about is what an empty landscape means: untapped whitespace in one reading, an absence of evidence in another.
No experiment has been published in which a KAT6 inhibitor extended lifespan or healthspan, and direct evidence that KAT6 inhibition modulates the senescence-associated secretory phenotype is absent from the peer-reviewed literature.	3	The longevity review states it and then argues past it, calling the gap an opening for a first-in-class position. The others state it and stop.
The MOZ/MORF complex is the real drug target: KAT6A and KAT6B sit in the same tetramer with BRPF1, ING5 and MEAF6.	2	The STRING interactomes of the two paralogs are the same list in a different order.
Inhibiting KAT6 induces cellular senescence rather than clearing it, and does so without DNA damage (Baell et al., 2018).	4	Agreed as fact by all four, and sharply disputed as a virtue. It is the finding the whole aging case turns on, and the two reports that do not state it do not contradict it either.

Counted by hand across the source documents.

The reports this page is built from.
Report	Produced by	What it covers	Length	Position
Target evaluation	PandaOmics Agents	Titled an indication prioritization, and the only report in the pack that also characterizes the target itself. 1,000 indications per target across 14 therapeutic areas, plus target characterization from UniProt, PDBe, gnomAD, ChEMBL, GWAS Catalog, ClinVar, Open Targets, Reactome, STRING, Human Protein Atlas and Ensembl Compara.	Web page	argues for, with conditions
Longevity evidence review	PandaClaw longevity agent	Hallmarks of aging, 27 aging clocks, GTEx expression against donor age, model-organism experiments, and the clinical pipeline.	16 pages	argues for
Indication prioritization	PandaOmics differential-expression prioritization	139 disease indications, ranked on differential expression of the two genes.	12 pages	argues for
Clinical evidence review	ClinicoClaw, Insilico clinical-trial intelligence	ClinicalTrials.gov and the internal curated trials dataset, plus a PubMed precedent search.	8 pages	argues against
Translation assessment	ClinicoClaw, Insilico clinical-trial intelligence	18 clinical assets from the internal trials dataset, cross-checked against ClinicalTrials.gov and PubMed.	6 pages	argues for, with conditions
LongevityClaw assessment	LongevityClaw target-evaluation agent	One question — whether inhibiting KAT6 would reduce the burden of cellular senescence — answered against 15 primary and review sources and a 233-clock reference set.	Web page	argues against

Titles, dates and page counts are as they appear on the documents.

How likely is it that a KAT6 inhibitor helps with senescence?
What it puts a number onKAT6i is the source’s shorthand for a KAT6 inhibitor.	Its estimate
KAT6i reduces senescent cell burden in normal aged tissue	< 10%
KAT6i raises p16 and senescent burden in proliferative compartments	~ 90%
Direction of effect holds in adult, non-embryonic tissue	~ 70%
A senescence-based aging indication is viable for this class	Very low
Cancer-prophylaxis healthspan hypothesis remains testable	Live

Statements and estimates are printed as the report gives them. LongevityClaw assessment, Verdict, Probability assessment

How to read these numbers

The numbers are the LongevityClaw assessment’s own. It is the only report in the pack to put figures on its own confidence — the other five give none — and nothing on this page averages or adjusts them.
The assessment does not show how it arrived at them. They carry the weight of a considered judgment by whoever read the evidence, not of a calculation that could be repeated, and they are reproduced here on that basis.
Two of the five answers are not numbers at all. A report that answers one row with a percentage and the next with “very low” has said two different kinds of thing, and both are printed as it wrote them rather than converted into figures it never gave.
One other report reaches the same place without a number. The clinical evidence review puts the “prior probability that a KAT6 inhibitor shows ‘solid, robust’ human anti-aging efficacy in the near term” at very low, and it got there by reading the clinical base rate rather than the mouse genetics. Two reports that read different literatures arrived at the same two words.

Open questions

The questions that are still open

Target evaluationCautionNone found

“No clinical trials were found for KAT6A or KAT6B in the ClinicalTrials.gov API query.”

Section 4.5, Clinical-Trial Landscape

Its own caveat: The report immediately adds that PF-07248144 may be registered under an alternative identifier or under KAT6 inhibitor terminology, then reports the null result anyway.

Clinical evidence reviewOpposesEight

Eight KAT6 programs were identified in the clinic, none of them in an aging or aging-related non-oncology indication.

page 1

Translation assessmentCautionEighteen assets

Eighteen clinical assets were retrieved from the internal trials dataset and cross-checked against ClinicalTrials.gov. All eighteen are oncology.

page 1

Reading for this site

Three reports looked for KAT6 programs in humans and returned none, eight and eighteen, and they did not look in the same place. The target evaluation queried ClinicalTrials.gov by gene symbol; the clinical review queried that registry by drug name, alongside Insilico’s curated trials dataset; the translation assessment counted records in that curated dataset and checked them back against the registry. ClinicalTrials.gov indexes interventions by drug name, so a gene-symbol query returns nothing for a target whose only clinical compound is registered as PF-07248144. The report diagnosed this itself and still printed the null. Nothing about the landscape is in dispute here — only whether one query was built to find it.

What settles it: Already settled, and the three figures were never counting the same thing. The target evaluation counted registry records matching a gene symbol and found none; the clinical review counted distinct programs and found eight, and its own source list gives nine registry identifiers for prifetrastat alone; the translation assessment counted asset records and found eighteen. One program can hold several records, so eight programs and eighteen records do not contradict each other. Treat the target evaluation’s Section 4.5 as unreported rather than as a finding.
If unresolved: If the null result had been taken at face value, the competitive picture would show an empty field where there are in fact eight programs, one of them with Phase 1 efficacy data.

Longevity evidence reviewSupportsFavorable

Senescence induction without DNA damage is presented as part of the anti-aging mechanism, alongside the hallmarks of aging and epigenetic-clock evidence.

pages 3 to 5

Target evaluationCautionRelevant, direction unresolved

“While the senescence-inducing property is an anti-cancer mechanism (arrested tumor growth), selectively targeting senescent cells in aging tissues (or modulating the senescence-associated secretory phenotype, SASP) opens a complementary therapeutic avenue.”

Section 3, Aging Indication Landscape

This site objects: The sentence moves from inducing senescence to clearing senescent cells without saying that these are opposite interventions, or presenting evidence that the compound does the second.

Clinical evidence reviewOpposesArguably the wrong direction

“The reports’ senescence-induction rationale is arguably the wrong direction for a longevity indication.”

page 1

LongevityClaw assessmentOpposesThe wrong direction, and it says so

“A KAT6 inhibitor is very unlikely to help with senescence, because it is a senescence-inducing agent.”

Verdict, Conclusion

Reading for this site

All four reports accept the same finding: KAT6 inhibition drives cells into irreversible arrest rather than clearing cells already arrested. They do not agree on the route. The target evaluation attributes the arrest to p21 without DNA damage; the others attribute it to de-repression of p16, and the LongevityClaw assessment lists an experiment to separate the two. Senescent cell burden is one of the things the aging field spends its money trying to reduce. Two of the reports name the tension outright and call the direction wrong. The target evaluation is the only one that tries to hold both, resolving it by changing the subject from senescence induction to senescent-cell clearance mid-paragraph. The LongevityClaw assessment is the only one to state the consequence outright, putting the chance that a KAT6 inhibitor lowers senescent-cell burden in aged tissue below ten percent. No report presents an experiment showing what a KAT6 inhibitor does to senescent cell burden in aged tissue, and one of them says why: no one has dosed a KAT6 inhibitor at sub-oncology exposure in an aged animal.

What settles it: A senescence and secretory-phenotype panel in aged animals, measuring senescent cell burden and the secreted profile after dosing. The target evaluation and the translation assessment both name this experiment. The LongevityClaw assessment specifies it: a chronic low-dose inhibitor in aged wild-type mice, at one fifth and one twentieth of the anti-tumor exposure, for six months, reading out p16 reporter burden across tissues, long-term hematopoietic stem cell lineage bias, neurogenesis in the subventricular zone and grip strength. None of the three reports it as having been done.
If unresolved: This is the single experiment that decides whether the aging thesis survives. It is also the last of the six checks the target evaluation lists in cost order, which is why the cheap direction-of-effect work should come first. That evaluation’s own summary calls the same panel one of its cheapest next steps; the disagreement is the source’s, and it is logged.

Translation assessmentCautionQuotes the numbers

Reports the objective response rate, the recommended Phase 3 dose and schedule, the hematological toxicity rates and the extent of H3K23 acetylation reduction, with the trial as the source.

page 2

Clinical evidence reviewOpposesDeclines to quote

The report states that its retrieval tools returned citation metadata rather than full text, and declines to report efficacy and safety magnitudes it could not ground.

page 4

Target evaluationCautionQualitative only

“PF-07248144, a KAT6A inhibitor, demonstrated clinical proof-of-concept in a Phase 1 dose-escalation trial in ER+/HER2− metastatic breast cancer with manageable safety and early anti-tumor activity (Mukohara et al., 2024).”

Section 9

Longevity evidence reviewSupportsRates safety without the numbers

Assigns a chronic-dosing safety rating without reproducing the trial’s toxicity figures.

page 12

LongevityClaw assessmentOpposesQuotes the numbers and reads them across

“This is an acceptable profile in metastatic breast cancer and an unacceptable one in an asymptomatic aging population.”

Clinical evidence, Human safety

Reading for this site

Two reports of the six print what the trial measured, and they agree: an objective response rate of 30.2 percent in combination, grade 3 to 4 neutropenia in 35.5 percent of patients, grade 3 to 4 anemia in 13.1 percent. Two others characterize the safety profile as manageable or favorable without showing the figures that characterization rests on. The report that could not reach the full text said so and withheld the numbers, which is the correct handling and leaves it looking thinner than the reports that asserted more with less.

What settles it: Read the primary publication. Mukohara et al. (2024), Nature Medicine, is cited by five of the six reports and is the origin of every clinical claim in the pack. Only one of them gives enough of the citation to find it.
If unresolved: Any decision memo drawing on this pack should quote the trial directly rather than inheriting a characterization of it.

Cheapest checks first

Four of these cost less to settle than the rest.

Listed in full under What would change the answer.

Target

The two proteins

KAT6A and KAT6B belong to the MYST family, the histone acetyltransferases numbered KAT5 to KAT8, and they are the two members of it that share the same four-protein complex and write the same histone mark. A compound that blocks one usually blocks the other, which is why the whole pack treats them as a pair rather than as two targets.

Where they differ is in the tissue they are busiest in. That difference is what the oncology case and the aging case each rest on, and it is the reason the two cases point at different organs.

0.08LOEUF for KAT6ALower means loss is less often tolerated. KAT6B is 0.09.

21solved structures for KAT6ABest resolution 1.4 ångström, against 3 structures for KAT6B.

51.8%identity between the twoIntentionally targeted. For a dual inhibitor this is the design basis, not an off-target risk.

459pathogenic KAT6A variantsClinVar records 2,124 variants for KAT6A in all.

The two genes side by side, as the target evaluation records them.
	KAT6A	KAT6B
Also known as	MOZ, MYST3	MORF, QKF, MYST4
UniProt	Q92794	Q8WYB5
Length	2004 amino acids	2073 amino acids
Mark written	H3K23	H3K23
Solved structures	21, best 1.4 ångström	3, best 1.6 ångström
Tolerance of loss (LOEUF)	0.08	0.09
ClinVar variants	2,124, of which 459 pathogenic	1,818, of which 346 pathogenic
Disease of loss	Many pathogenic variants are linked to KAT6A syndrome, a neurodevelopmental disorder.	Pathogenic variants are linked to Genitopatellar syndrome and to Say-Barber-Biesecker-Young-Simpson syndrome.
Busiest cell type	Neutrophils, 1367 normalized counts per million	Distal convoluted tubule cells, 244 normalized counts per million
Essential in DepMap	Not common-essential	Not common-essential
Mouse sequence identity	88.4%	—Not recorded. The target evaluation gives this figure for KAT6A only.

UniProt, NCBI Gene, the Protein Data Bank, gnomAD v4, ClinVar and the Human Protein Atlas, as cited by the target evaluation.

What the constraint statistics imply

LOEUF 0.08 for KAT6A and 0.09 for KAT6B places both among the most constrained genes in the genome, consistent with essential roles in hematopoiesis and development.
Very low LOEUF implies inhibition may be poorly tolerated at high doses, and the report calls the therapeutic window narrow.
Neither gene is common-essential in DepMap, which suggests complete inhibition is not broadly cell-lethal, and the Phase 1 safety profile reported for PF-07248144 was described as manageable.
KAT6A knockout in mice causes severe hematopoietic stem cell depletion (Katsumoto et al., 2006). KAT6B mutations cause Genitopatellar syndrome.

Figure 1

Moderate cross-reactivity riskLow cross-reactivity risk

How close the nearest relatives are, and how the evaluation rates each one.

Ensembl Compara, as reported in the target evaluation.

What the evaluation says to test against

Selectivity profiling against KAT8 and KAT7 is recommended.

How strong the human genetics really is

The evaluation grades its own genetic support as moderate / indirect. Human genetic support for the lead oncology indications is association-level. The genome-wide association study traits are not fine-mapped to KAT6A or KAT6B as the causal gene. The strongest genetic evidence is the recurrent KAT6A chromosomal translocation in acute myeloid leukemia, which is direct oncogenic driver evidence.

Structure

What the solved structures actually contain

KAT6A reading a crotonylated histone H3 tail

X-ray diffraction at 1.4 ångström. Protein Data Bank entry 5B78

Chain A is the KAT6A double plant homeodomain finger: two small folds, each held in shape by zinc, which together clamp the tail of histone H3. Chain B is that tail, its first twenty-two amino acids, and the residue drawn in blue is its lysine at position fourteen carrying a crotonyl group. The purple spheres are the four zinc ions; they hold the fold together and take no part in any reaction. The protein crystallized here carries two engineered amino acid substitutions, so it is a variant of the human sequence rather than the wild type.

KAT6B reading a butyrylated histone H3 tail

X-ray diffraction at 1.6 ångström. Protein Data Bank entry 5U2J

The same module in KAT6B, the protein the rest of this section treats as the other half of the pair. Chain A is the double plant homeodomain finger and chain C is the first sixteen amino acids of histone H3; the residue in blue is again lysine fourteen, this time carrying a butyryl group rather than a crotonyl one. The crystal holds two copies of the complex and the second copy is left out of this view. Four zinc ions hold each copy of the fold.

KAT6A holding the free end of a histone H3 tail

X-ray diffraction at 1.47 ångström. Protein Data Bank entry 3V43

The KAT6A module again, and the entry whose fine print matters. The sequence deposited with it names an acetylated lysine at position fourteen, but the coordinates stop at residue seven, so that lysine is not resolved and nothing in this view is highlighted as the mark. What is present is the far end of the same grip: the free start of the histone H3 tail and the arginine beside it, lying against the surface of the module. The zinc ions are structural, and the only other group in the file is an acetate ion left over from the crystallization.

All three coordinate sets cover the same piece of the protein: the double plant homeodomain finger, the module that reads a histone tail and holds the enzyme on it. It is not the MYST acetyltransferase domain that writes the mark, and no inhibitor is bound in any of the three. A chemist looking for the pocket a compound would occupy will not find it in these files; what is here is the grip.

Coordinates as deposited in the Protein Data Bank. All three identifiers, and the resolutions printed with them, are ones the target evaluation lists.

Druggability

What can be built against it, and who is already building

Knowing the pair is worth blocking is not the same as knowing a molecule can. This section holds what the target evaluation found about the protein as a thing to build against: the solved structures a chemist would work from, the patent families already filed, and the compounds other companies have taken into people.

The patent count is the part of it that changes the picture most. A field with no trials in it can still be a field that several organizations are working hard, and composition-of-matter filings are visible years before a trial is.

One listed structure is not KAT6A

Each of the eight identifiers in the table below was looked up in the Protein Data Bank’s entry record for each identifier, retrieved 2026-08-12. Seven of them return the protein the evaluation names. One does not. 8A27 is the epidermal growth factor receptor kinase domain bound to an isoindolinone acetamide, solved by X-ray diffraction at 1.07 ångström. No KAT6A chain is deposited under it. The table and the chart below print that row as the evaluation printed it, because this page transcribes its sources rather than correcting them in place. The full entry is in the corrections section.

The eight structures the evaluation lists one by one. Resolution is how finely the structure was resolved, measured in ångström, where a smaller number is a sharper picture.
Structure	Protein	How it was solved	Resolution, ångström	Share of the protein
5B78	KAT6A	X-ray diffraction	1.4	6%
3V43	KAT6A	X-ray diffraction	1.47	6%
7Y43	KAT6A	X-ray diffraction	1.5	4%
5B77	KAT6A	X-ray diffraction	1.55	6%
8A27	KAT6A	X-ray diffraction	1.55	13%
5U2J	KAT6B	X-ray diffraction	1.6	5%
6OIE	KAT6B	X-ray diffraction	2.08	5%
8E4V	KAT6B	Solution NMR	—	4%

KAT6A: 21 solved in all, five listed here, solved by X-ray diffraction and Solution NMR. KAT6B: three listed. A dash in the resolution column is a structure solved by a method that does not report one.

Figure 2

KAT6AKAT6B

How much of each protein its solved structures actually cover. The largest of them reaches 13 percent of the sequence, so every one of them is a piece of the protein rather than the whole of it.

Coverage is the share of the full-length sequence a deposited structure spans, as the evaluation records it.

What the KAT6A structures cover, and what has to be modeled

Coverage is per-domain — primarily MYST-HAT domain and PHD fingers.

What the KAT6B structures cover, and what has to be modeled

The KAT6B HAT domain can be modeled by homology from KAT6A (~52% identity in the MYST domain).

The patent field

The evaluation names seven holders with filings against this target. It calls the field highly active. Freedom to operate is the right to make and sell a compound without infringing a patent somebody else holds, and it is settled by the chemical series a program runs on rather than by the protein it aims at.

The seven patent holders the evaluation names, and the eight filings it lists for them.
Holder	Filings	Chemical series
Pfizer	EP4181920B1, US12545669B2	benzisoxazole sulfonamides
CTXT Pty Ltd	US11911372B2	thiadiazine derivatives
Hangzhou Inogate	JP7749263B2	—
Hengrui	WO2023016484A1	macrocyclic compounds
Isosterix	US11976075B2	—
Xuanzhu / Shandong	CN116621859A	tricyclic scaffolds
Beijing Conlans	JP2026512835A	—

Fifteen or more patent families, with filings running through 2024 to 2026. A dash means no chemical series was recorded for that holder, which is the case for three of seven.

What the evaluation concludes about freedom to operate

Freedom-to-operate requires careful scaffold differentiation.

Who else is working on this

The evaluation looked for a clinical program against four related proteins, KAT6B, KAT8, KAT7 and KAT5, and found none against any of them. That is a search of trial registries rather than of the world: a compound nobody has registered is invisible to it.

The competitive picture in the evaluation’s own words

No same-family drug has been approved, failed, or withdrawn — the KAT6 inhibitor class is entirely novel.
PF-07248144 (Pfizer) is the only known clinical-stage program, currently in Phase 1 for ER+/HER2− metastatic breast cancer (Mukohara et al., 2024).
WM-8014 and WM-1119 are academic tool compounds from the Walter and Eliza Hall Institute (Baell et al., 2018).
Multiple companies are filing composition-of-matter patents (see IP landscape above), suggesting active preclinical pipelines from Hengrui, Hangzhou Inogate, CTXT, Isosterix, Beijing Conlans, and Xuanzhu.

Three places the evaluation says a program here could differentiate itself

Hitting both targets simultaneously, reducing resistance risk
Accessing KAT6B-dominant indications (lymphoma, neurodegeneration)
Exploiting the aging/senescence biology unique to dual inhibition

Expression

Which diseases carry the signal

The indication report compared KAT6A and KAT6B expression in diseased tissue against matched normal tissue across 139 diseases, then sorted them by whether the two genes move together. A positive log2 fold change means the gene is more highly expressed in the diseased tissue.

The sort matters more than any single value. Where both genes are raised, blocking the enzyme has an obvious direction of effect. Where both are lowered, it does not, and the report has to argue that reduced expression is compensation rather than a reason to leave the pathway alone. That argument is the weakest load-bearing step in the whole pack.

Indication prioritization, pages 1 to 2

139diseases comparedEvery disease with expression data for at least one of the two genes.

9with both genes raisedTier 1, the group the report calls the strongest case for an inhibitor.

39classed as age-relatedAgainst 66 in oncology.

−0.509largest change in either geneKAT6B in Coronary artery disease, at −0.509. The largest movement the other way is KAT6A in Familial amyloid neuropathy, at +0.425.

Indication prioritization, pages 1, 2 and 5

This chart is a redraw, not a copy

The quadrant labels on the original are mirrored through the origin, so a disease with both genes raised is drawn in the corner marked as both lowered. The values behind the figure are right; only its labels are wrong. The chart below carries the corrected labels. The full entry is in the corrections section.

Indication prioritization, Figure 2, page 3 of the indication report

Figure 3

Tier

Area

38 diseases shown

Tier 1, both raisedTier 2, both loweredTier 3, discordantTier 4, one gene measured, in the table only

Each dot is one disease. The buttons above narrow the chart and the table below it together, so a tier can be read as points and as numbers at once.

Drawn in place of Figure 2, KAT6A versus KAT6B concordance, on page 3 of the indication prioritization.

Values as printed in the tier tables of the indication report. A point needs both genes, so eleven of these diseases are in the table and not on the chart: the report prints one gene’s value for nine of them and neither gene’s for two. Indication prioritization, pages 2 to 5

Every disease the report’s tier tables name, with the page it was read from.
Disease	Area	KAT6A	KAT6B	KAT6A p‑value	KAT6B p‑value	Tier	Page
Parkinson’s disease	Age-related	+0.414	+0.326	2.73e-7	0.001	1	2
Alzheimer’s disease	Age-related	+0.364	+0.290	1.02e-14	2.78e-10	1	2
Medulloblastoma	Oncology	+0.184	+0.414	5.24e-16	1.08e-40	1	2
Azoospermia	Other	+0.243	+0.299	5.23e-6	2.47e-6	1	2
Invasive lobular carcinoma	Oncology	+0.186	+0.274	0.037	0.013	1	2
Oligodendroglioma	Oncology	+0.158	+0.297	6.49e-15	2.32e-12	1	2
Adrenal gland pheochromocytoma	Oncology	+0.157	+0.250	9e-4	4.3e-8	1	2
Astrocytoma	Oncology	+0.147	+0.079	9.96e-8	0.018	1	2
Kaposi’s sarcoma	Oncology	+0.085	+0.116	0.044	0.029	1	3
Hypertension	Age-related	−0.471	−0.394	—	—	2	4
Diffuse scleroderma	Age-related	−0.285	−0.426	—	—	2	4
Polycythemia vera	Oncology & age-related	−0.269	−0.403	—	—	2	4
Primary myelofibrosis	Oncology & age-related	−0.365	−0.221	—	—	2	4
Chronic myelogenous leukemia	Oncology	−0.278	−0.243	—	—	2	4
Diabetic nephropathy	Age-related	−0.264	−0.217	—	—	2	4
Burkitt’s lymphoma	Oncology	−0.288	−0.145	—	—	2	4
Hodgkin’s lymphoma	Oncology	−0.181	−0.247	—	—	2	4
Diffuse large B-cell lymphoma	Oncology	−0.232	−0.190	—	—	2	4
Type I diabetes mellitus	Age-related	−0.236	−0.177	—	—	2	4
Psoriasis	Age-related	−0.216	−0.180	—	—	2	4
Melanoma	Oncology	−0.143	−0.247	—	—	2	4
Cirrhosis of liver	Age-related	−0.177	−0.171	—	—	2	4
Idiopathic pulmonary fibrosis	Age-related	−0.137	−0.164	—	—	2	4
Actinic keratosis	Age-related	−0.160	−0.115	—	—	2	4
Age-related macular degeneration	Age-related	−0.087	−0.101	—	—	2	4
Dilated cardiomyopathy	Age-related	−0.115	−0.048	—	—	2	4
Systemic scleroderma	Age-related	—	—	—	—	2	5
Juvenile idiopathic arthritis	Age-related	—	—	—	—	3	5
Sporadic amyotrophic lateral sclerosis	Age-related	+0.112	−0.061	—	—	3	5
Amyotrophic lateral sclerosis	Age-related	+0.364	—	—	—	4	5
Coronary artery disease	Age-related	—	−0.509	—	—	4	5
Familial amyloid neuropathy	Age-related	+0.425	—	—	—	4	5
Familial amyotrophic lateral sclerosis	Age-related	+0.166	—	—	—	4	6
Multiple sclerosis	Age-related	+0.204	—	—	—	4	5
Myocardial infarction	Age-related	—	−0.407	—	—	4	5
Pick disease	Age-related	+0.299	—	—	—	4	5
Portal hypertension	Age-related	—	−0.505	—	—	4	5
Stroke	Age-related	—	−0.226	—	—	4	5

Sorted by tier, then by the report’s own rank within the tier. The bar under each fold change draws that number on one scale shared by both genes: it runs right from the zero line where the gene is raised in diseased tissue and left where it is lowered, and reaches full length at half a log2 unit. Significance values are reproduced as the report prints them, and it prints them for the first tier only, so a dash is a value the source does not give rather than a result that missed a threshold. Click a column heading to sort. Indication prioritization, tier tables, pages 2 to 6

Figure 4

KAT6A is raised in all seven neurodegenerative conditions surveyed. KAT6B has a printed value in only three of them, and agrees in two: in sporadic amyotrophic lateral sclerosis it is slightly lowered while KAT6A is raised. The two conditions where both genes rise together are also the two the report puts in its top tier.

A disease with no printed value for a gene is marked as such rather than plotted at zero. Use the legend to hide either gene. Indication prioritization, page 5

Figure 5

Median fold change across experiments for the cancers the report charts separately. The report printed five of these in bold red; those are highlighted here.

Read from the value labels printed on the source figure, not from a table of values. This is a different statistic from the tier tables and the two should not be compared directly. Indication prioritization, Figure 6, page 9

What the two figures do not settle

KAT6A is raised in all seven neurodegenerative conditions surveyed, though KAT6B is printed for only three of them and moves the other way in one. That is the strongest single observation in the indication report, and it is still an observation about messenger RNA in diseased tissue. The Clinical evidence review’s objection stands: a fold change of this size is not evidence that lowering the enzyme’s activity changes the disease.

Ranking

Where age-related disease sits in the ranking

The same run scored both genes against roughly 1,000 indications using 23 measures drawn from disease datasets, from the published literature and from grant funding. Language-model scores were excluded, and umbrella terms such as cancer and sarcoma were removed so that they could not crowd the top of the list.

This is a different question from the expression comparison. Expression asks whether the genes move in diseased tissue. The ranking asks how much of everything already known about a gene points at a given disease. A disease can score well on one and poorly on the other, and the aging indications do exactly that.

Figure 6

Falls under the composite ranking

The same diseases under both methods. Diseases at the top of the expression tiers sit in the hundreds once everything else known about the genes is counted.

Left, the tier tables of the indication report. Right, the composite rank out of 1,000 from the target evaluation, for whichever of the two genes the ranking placed the disease under, taking the higher position where it placed both. Each gridline on the right-hand scale marks ten times the position of the one before it, so the top of the field is spread out and the tail is compressed.

Every age-related indication the evaluation ranked, with its position out of 1,000.
Indication	KAT6A	KAT6B	Stronger gene	What drives it
Cardiovascular disease	#83	#42	KAT6B	GWAS: body mass index for KAT6B, bone density for KAT6A
Alzheimer’s disease	—	#132	KAT6B	GWAS: Alzheimer disease for KAT6A, educational attainment for KAT6B
Postmenopausal osteoporosis	#676	#890	KAT6A	GWAS: bone density for KAT6A
Skin aging	—	#669	KAT6B	Epigenetic changes in skin aging
Parkinson’s disease	—	#696	KAT6B	KAT6B expressed in brain neurons
Sarcopenia	#750	—	KAT6A	Age-related muscle wasting
Hutchinson-Gilford progeria syndrome	—	#812	KAT6B	Accelerated aging model
Idiopathic pulmonary fibrosis	—	#814	KAT6B	Senescence in fibrotic lung
Age-related macular degeneration	#954	—	KAT6A	Retinal aging
Metabolic syndrome	#989	—	KAT6A	GWAS: type 2 diabetes for KAT6A

A dash means the gene did not rank the indication at all.

How to read those positions

KAT6B carries the aging signal more strongly than KAT6A, with better ranks for cardiovascular disease, Alzheimer’s, Parkinson’s and progeria. That fits its higher expression in brain neurons and kidney tubule cells. The ranks themselves are the important detail: the best aging indication sits at 42 out of 1,000, and eight of the other nine sit past 600.

The indications the ranking puts first, before any age-related filter is applied, with their positions out of 1,000.
Indication	KAT6A	KAT6B	Measures carrying the score
breast cancer	#3	#4	Evidence, Trend, Attention, Matrix factorization
leukemia	#5	#3	Grant funding, Attention, Graph walk, Matrix factorization
acute myeloid leukemia	#4	#15	Attention, Grant funding, Interactome, Causal inference
lymphoma	#24	#11	Graph walk, Matrix factorization, Interactome
non-Hodgkin’s lymphoma	#28	#12	Interactome, Matrix factorization
hepatocellular carcinoma	#17	#25	Mutated sub-modules, Interactome, Graph walk
chronic lymphocytic leukemia	#38	#16	Interactome, Graph walk, Expression
breast carcinoma	#32	#32	Matrix factorization, Evidence, Relevance

The full list runs to twelve; the eight highest-ranked are shown. Indication names are printed with the capitalization the evaluation gives them, which is not the capitalization the indication report uses for the same diseases.

Evidence, Trend and Relevance carry no weight in the evaluation’s own appraisal

Literature/attention scores … reflect research activity, not biological validation — they are weight-0 for trust.
Trust rests on independent high-weight lines that agree, not the count of correlated scores.

The gap the evaluation states in its own words

“Direct evidence for KAT6A/KAT6B inhibition extending lifespan, modulating SASP, or treating specific aging-associated diseases remains absent from the peer-reviewed literature.”

What the evaluation says its own ranking cannot do

DE uses the PandaOmics Expression score (raw logFC unavailable in this environment).
GWAS/mutation are association-level, not fine-mapped.
Single prioritization source; scores are relative within PandaOmics.
The aging indication prioritization relies on term-matching and PandaOmics ranking — no dedicated aging/longevity database was available.
PF-07248144 is not yet registered in ChEMBL, so clinical tiering may underrepresent the maturity of the breast cancer indication.

Rationale

Why these indications, and what would settle them

A rank is a position in a list, and a position is not a reason. This section is the target evaluation’s own account of why the enzyme should matter in the diseases it put at the top, and what it would run next to find out whether it does.

It is reproduced rather than summarized. The reasoning is the part of that report a reader can argue with, and paraphrasing it would put this page between the reader and the argument.

The evaluation makes five mechanistic arguments and records five next steps, and it does not name the indications the same way in both: one of the headings appears word for word in the other list. They are set out below in the order the evaluation gives them rather than paired up.

The five mechanistic arguments the evaluation makes, in the order it makes them.
What it is about	What the evaluation argues
Acute myeloid leukemia	KAT6A/MOZ was identified through its involvement in recurrent AML chromosomal translocations. The MOZ-TIF2 fusion (t(8;8)(p11;p12)) drives leukemogenesis by sequestering CBP, impairing p53, and repressing cellular senescence (Carapeti et al., 1998; Kindle et al., 2005; Largeot et al., 2016). MOZ-TIF2 displays KAT6-dependent H3K23 propionylation and overexpresses developmental genes (Smolko et al., 2024). WM-1119 effectively targets KAT6A-rearranged AML in preclinical models (Sheridan et al., 2024). Wild-type MOZ is essential for maintenance of HSCs — conditional knockout depletes long-term repopulating cells (Katsumoto et al., 2006).
ER+ breast cancer	KAT6A is amplified/overexpressed in ER+ breast cancer. KAT6 inhibition induces cellular senescence and proliferative arrest through p21 upregulation, providing a non-cytotoxic anti-cancer mechanism (Baell et al., 2018). PF-07248144, a KAT6A inhibitor, demonstrated clinical proof-of-concept in a Phase 1 dose-escalation trial in ER+/HER2− metastatic breast cancer with manageable safety and early anti-tumor activity (Mukohara et al., 2024).
Lymphoma and other hematological malignancies	Both KAT6A and KAT6B are involved in B-cell development and lymphoid biology. MOZ-rearranged leukemia is driven through MLL-mediated activation of CpG-rich promoters (Miyamoto et al., 2020). The MOZ/MORF complex regulates HOX gene expression and stem cell self-renewal programs relevant across hematological malignancies (Yang & Ullah, 2007; Huang et al., 2016).
Cellular senescence and aging	The landmark Baell et al. (2018) study demonstrated that WM-8014 and WM-1119 induce senescence without DNA damage or apoptosis — an irreversible growth arrest phenotype mechanistically distinct from cytotoxic agents. KAT6A acetylates p53, promoting premature senescence (Rokudai et al., 2013). The MOZ-TIF2 oncoprotein actively represses senescence (Largeot et al., 2016), establishing KAT6A as a senescence rheostat. This positions KAT6 inhibitors at the intersection of cancer and aging biology: the same mechanism that arrests tumor growth could, in principle, modulate senescent cell accumulation in aging tissues.
Neurodegeneration	KAT6B is enriched in brain excitatory neurons and choroid plexus epithelial cells. KAT6A has GWAS associations with Alzheimer disease and dementia. However, direct experimental evidence linking KAT6 inhibition to neuroprotection is absent — this remains the weakest mechanistic link and requires dedicated investigation.

Every sentence in the right-hand column is the evaluation’s own, citations included. None of it was checked against the papers it names.

The five indications the evaluation carries forward. It records the same verdict against every one of them, conditional.
Indication	What would have to happen next	What would rule it out
Breast cancer (ER+)	Wait for the PF-07248144 Phase 1 expansion data, and run drug-target Mendelian randomization for a causal KAT6A effect on breast cancer.	PF-07248144 fails to show objective response.
Acute myeloid leukemia	WM-1119 or dual inhibitor efficacy in MOZ-fusion AML PDX models	No proliferation arrest in MOZ-TIF2+ primary samples.
Non-Hodgkin’s lymphoma	Cell-line panel screen (DLBCL, MCL)	No single-agent activity in lymphoma lines.
Cardiovascular disease (aging)	Senescence/SASP panel in ApoE-KO mice	No reduction in vascular senescent cell burden.
Alzheimer’s disease (aging)	KAT6B expression profiling in AD brain tissue	No differential expression in AD vs control.

Every one of these has a recorded result that would rule it out. Both columns carry the evaluation’s own words, apart from one step written out here because the evaluation set the relation as an arrow.

Mechanism

The case that this target sits in the biology of later life

The longevity review makes its case in two parts. First, that both genes sit on pathways already recognized as drivers of aging. Second, that blocking them pushes damaged cells into a permanent growth arrest without killing the healthy cells around them.

The first part is well supported and largely uncontested. The second is the load-bearing claim, and the review states the objection to it before answering: the arrest it wants to induce is the same process that other aging programs spend their money removing.

Longevity evidence review, pages 5 and 3

3hallmarks touched by KAT6AEpigenetic alterations, cellular senescence and genomic instability. KAT6B is associated with one, epigenetic alterations.

5arguments for a therapeutic windowEach argument answers the objection that healthy cells are affected too.

0lifespan experiments runNo published study has dosed a KAT6 inhibitor and measured how long anything lived.

4age-related resources checkedNone of them lists either gene.

The three hallmarks the review connects KAT6A to.
Hallmark	What the review claims	What the claim does not cover	Confidencereview’s own
Epigenetic alterations	Both genes are themselves epigenetic regulators: they acetylate histone H3 at lysines 9, 14 and 23, which changes how open the chromatin is at thousands of gene loci.	Being a feature in a clock says where a gene sits in a statistical model. It does not say what happens to predicted age when the gene is inhibited.	5 of 5
Cellular senescence	KAT6A normally holds the CDKN2A locus shut, keeping p16 and p14 low and cells proliferating. Inhibiting KAT6 re-opens that locus, p16 and p14 rise, the retinoblastoma and p53 pathways switch on, and the cell arrests permanently in G1.	No finding in the pack is more contested. Senescent cell burden is one of the things aging medicine spends its money trying to reduce, and the same mechanism is being counted here as a benefit.	5 of 5
Genomic instability	H3K9 acetylation, the mark KAT6A deposits, obstructs activation of the ATM kinase and impairs the DNA damage response in normal stem cells.	The experiment reduced the mark directly. No KAT6 inhibitor was used, and no aging animal was involved.	3 of 5

Confidence is the review’s own five-point rating, reproduced rather than recomputed. Longevity evidence review, page 5

The review states the objection to its own thesis and answers it in five parts: that KAT6 inhibitors push damaged and pre-cancerous cells into senescence far more readily than normal cells, so the selectivity is a matter of degree rather than an on-off switch.
The argument	As the review puts it	Where it stops
Cancer cells carry extra copies of KAT6A and depend on them	KAT6A sits inside the 8p11-p12 amplicon, present in 10 to 15 percent of breast cancers. Cells that carry the amplification have built their transcriptional program around unusually high KAT6A activity.	The review gives the amplicon frequency as 12 to 15 percent in its clinical section and 10 to 15 percent here, citing the same paper.
KAT6B backs KAT6A up in normal cells	The two proteins share about 60 percent of their amino acid sequence and the same domain layout, so endogenous KAT6B can absorb partial loss of KAT6A in a normal cell.	That rescue is developmental, genetic and in mice. It shows the backup exists; it does not show a drug leaves it intact.
The p16 checkpoint fires hardest in cells already under strain	Cells carrying activated oncogenes push p16 upward constantly and are held in check only by KAT6A. Remove that restraint and p16 crosses the arrest threshold. Normal cells have no such pressure, so a modest rise stays below the line.	The parallel is an argument by analogy. No experiment in the pack measures where that threshold sits in normal tissue during KAT6 inhibition.
Human safety data show normal tissue tolerating the drug	In the Phase 1 trial, more than 70 percent of the H3K23 acetylation mark was removed in normal blood cells as well as in tumor, and the toxicity that followed was confined to reversible myelosuppression.	Manageable for months in metastatic breast cancer is a different bar from tolerable for years in a healthy adult. The translation assessment makes exactly this objection.
Halving the gene is safe and still protects against cancer	Mice with one working copy develop normally, and survive roughly four times longer when challenged with MYC-driven lymphoma, from 105 days to 413 days.	Arboleda-Tham syndrome involves developmental delay. The review reports normal lifespan alongside that, without weighing the two.

The five arguments are numbered in the review; the order is preserved. Longevity evidence review, page 3

The review’s own concession

The review is explicit that the selectivity is imperfect.

The compounds that established the mechanism, WM-8014 and WM-1119, were shown to induce senescence in non-cancerous cells: mouse embryonic fibroblasts and IMR-90 fibroblasts.
Grade 3 neutropenia in 39.5 percent of patients confirms that normal myeloid progenitors are affected.
KAT6A is required for normal hematopoietic and neural stem cell maintenance.
Its answer is a comparison rather than a rebuttal: CDK4/6 inhibitors cause grade 3 or 4 neutropenia in up to 65 percent of patients and became standard of care anyway, because the window was wide enough.

Longevity evidence review, page 3

Associations

What the clock and expression data actually show

Two bodies of data carry the aging argument. Epigenetic clocks, which predict age from methylation at particular sites, include KAT6A or KAT6B among their inputs more often than chance would suggest. And in donated tissue from people who were not ill, expression of the two genes changes with the donor’s age.

Both are associations. Neither shows that changing the enzyme changes the aging process, and the review is explicit that no published work links a KAT6 inhibitor to an epigenetic clock reading.

Longevity evidence review, pages 6 and 11

27clocks include one of the genesAcross 78 separate entries.

24of those include KAT6BAgainst 6 for KAT6A.

−0.341the review’s strongest single signalKAT6B in the mammalian lifespan predictor, ranked 12 of 145 within that clock.

818donors in the largest tissue sampleMuscle, skeletal, measured for KAT6A. The smallest of the samples drawn here holds 255 donors.

Longevity evidence review, pages 6, 8, 10 and 11

The review’s own summary of this evidence

The review reports “5 of 8 key evidence streams support KAT6 inhibition for anti-aging”. The eight streams behind that count are listed below, with the direction each one points.

Longevity evidence review, page 11

The eight evidence streams the review’s verdict is counted from.
Clock or dataset	Gene	Coefficient	Rankwithin the clock	What the review reads into it
Mammalian lifespan predictorSupports	KAT6B	−0.341	12 of 145	Species whose KAT6B locus is more heavily methylated, and so more silenced, live longer.
Mammalian sexual maturitySupports	KAT6B	+0.676	8 of 227	More KAT6B silencing goes with later maturation, which across species goes with longer life.
PASTA age-shiftSupports	KAT6A	−1.28e-05	5313 of 8112	KAT6A expression tracks with an older transcriptomic age.
REG chronological ageSupports	KAT6A	+3.80e-04	979 of 8112	KAT6A expression rises with chronological age.
Pan-mammalian age, relative to lifespanSupports	KAT6B	−0.137	123 of 613	More KAT6B silencing goes with a younger position in the species lifespan.
GrimAge, versions 1 and 2Caution	KAT6B	+192.76	37 of 123	KAT6B methylation, and so silencing, rises as biological age advances. The review reads this as the body already doing what the drug would do; this page reads it as equally consistent with the drug pushing a mark that is already moving.
Peters TRAP blood transcriptomeCaution	KAT6B	−0.032	1473 of 11908	KAT6B expression falls with age in blood, so inhibition would push further in a direction age has already taken.
CD4 naive T-cell deconvolutionOpposes	KAT6B	−0.098	13 of 208	KAT6B silencing goes with fewer naive CD4 T-cells, which is a marker of an aging immune system. The review flags this for monitoring during chronic dosing.

Coefficients, ranks and readings are the review’s own, from its integrated table, except where a row says this page reads it otherwise. The clocks do not share a sign convention: in an age-shift model a negative coefficient means older, and in a chronological-age model a positive one does. Entry and clock totals are from the two per-gene sections. Longevity evidence review, page 10

Figure 7

Gene

With age

18 tissue measurements shown

KAT6AKAT6B

Bars run left or right of zero according to whether expression rises or falls with donor age, and are ordered by how strong the correlation is. Every correlation here is weak: the widest bar, skin at 0.243, accounts for under six percent of the variation between donors.

Tissue from non-diseased donors in the GTEx tissue-expression database, version 10. Readings are transcripts per million, log-transformed after adding one so that zero readings stay on the scale, correlated against binned donor age with Pearson’s coefficient. The review gives its retrieval date in a form that reads as either 12 November or 11 December 2024. Binned intervals were used for commercial licence compliance. Longevity evidence review, page 11

Neither gene moves against the other

Seven tissues carry a value for both genes, and in none of them does one rise while the other falls: they rise together in three, fall together in two and in the remaining two at least one of them does not move.

The review reads the KAT6A rise in skin and lung as a pro-aging role that inhibition would reverse. The two brain measurements, in the tissue that matters for the neurodegenerative indications ranked first elsewhere in the pack, show no change with age.
KAT6B falls with age in heart and artery, which the review ties to published evidence of an age-related KAT6B decline in hematopoietic stem cells.

Longevity evidence review, page 11

Neither gene appears in any curated aging resource the review checked.
Resource checked	KAT6A	KAT6B
ClinicalTrials.gov, aging trials	not listed	not listed
Geroprotectors database	not listed	not listed
GenAge database	not listed	not listed
Aging-related publications	not listed	not listed

Checked by the review at the date it was produced. Longevity evidence review, page 5

The same table, read two ways

The review presents this as a gap it aims to close, and as a first-mover advantage.
The same table can be read as four independent curation efforts having looked at this literature and not found enough to include.

No lifespan experiment has been run with a KAT6 inhibitor. The review substitutes evidence from other acetyltransferase inhibitors that touch the same histone marks.
Study	Model	What it found	How the review connects it
Huang et al., Aging Cell 2020	Yeast and human fibroblasts	Acetyltransferase inhibitors, including epigallocatechin gallate, anacardic acid, garcinol and curcumin, extended replicative lifespan by 29 to 50 percent and reduced senescence markers.	Those enzymes deposit H3K9 and H3K18 acetylation, marks a KAT6 inhibitor also reduces.
Huang et al., Aging Cell 2020	Yeast	Lifespan extension under caloric restriction depends on GCN5.	The review reads acetyltransferase inhibition as partly reproducing caloric restriction.
Kirfel et al., 2020	Pea aphid	Inhibiting histone acetylation and deacetylation enzymes changed longevity, development and fecundity.	Offered as evidence that the axis holds across species.
Morselli et al., Aging 2009	Several	Spermidine, which inhibits acetyltransferases, extends lifespan by inducing autophagy.	Offered as convergent evidence.

None of these compounds is selective for KAT6. The four named natural products inhibit several acetyltransferases and much else besides, which is why the review presents them as precedent rather than as evidence about this target. Longevity evidence review, page 12

Clinic

What has been tested in people

The two clinical sources searched trial registries and the published literature for anything that has put a KAT6 inhibitor into a person. They found a crowded oncology field and nothing at all outside it.

That asymmetry is the single most consequential fact in this pack. It means the mechanism is no longer speculative in humans, and it also means that every claim about aging rests on evidence collected in people with metastatic cancer.

Clinical evidence review, page 1

18clinical assets retrievedThe source’s own count of records retrieved from its internal trials dataset. It does not list them one by one, so the note under the table sets it beside the nineteen identifiers this pack prints.

100%of them in oncologyEvery one, without exception.

0trials in age-related diseaseNo registered or published human study in aging, neurodegeneration or fibrosis.

1with published clinical resultsOne trial, one journal paper. Everything else is a registry entry.

Clinical evidence review, page 1

The assessment’s own framing

“The first-mover ‘gap’ your internal reports identify is real, but it is a gap in evidence, not just in competition.”

Translation assessment, page 1

Figure 8

Stage

10 programs shown

In Phase 3In Phase 1 and 2 or Phase 1

Bar length is the number of registered studies retrieved for each program, which is a measure of how much a sponsor has committed rather than of how well the drug works. Of the programs drawn here, one is in Phase 3; one in Phase 1 and 2; five in Phase 1. SYH-2095, BAY-184 and Prelude KAT6A degrader are in the table but not in this figure: they were retrieved from internal records and carry no registry identifier to count.

Registry records, with compound status cross-checked against the Longevity evidence review. Clinical evidence review, page 3

One row per KAT6 program in the pack. Prifetrastat’s six healthy-volunteer clinical-pharmacology studies are held out and listed under the table. The two inobrodib trials in the pack are not here, because inobrodib inhibits p300 and CBP rather than KAT6 and appears in the sources as a comparator.
Program	Sponsor	Stage	Setting	Registry entriesas retrieved
PF-07248144 (prifetrastat)	Pfizer	Phase 3	ER-positive, HER2-negative metastatic breast cancer, with fulvestrantPhase 3 recruiting, 400 patients, progression-free survival by blinded independent central review as the primary endpoint. The only asset in Phase 3 and the only one with a peer-reviewed clinical publication.	NCT04606446, NCT07062965, NCT07340619
HRS-2189	Jiangsu Hengrui	Phase 1 and 2	Breast cancer, with planned prostate and colorectal studiesRecruiting; the prostate study is planned. The broadest indication program after Pfizer’s.	NCT05851092, NCT06679036, NCT06738745, NCT07061210
BG-75202	BeOne Medicines	Phase 1	Advanced solid tumors and hematological malignanciesRecruiting. The longevity review lists this as investigational new drug stage; the registry records two Phase 1 studies.	NCT07222267, NCT07619287
HLX-97	Shanghai Henlius	Phase 1	Advanced solid tumorsRecruiting. Not present in the internal reports.	NCT07480681
IDE-574	Ideaya Biosciences	Phase 1	ER-positive, HER2-negative breast cancer, with fulvestrantRecruiting. The longevity review refers to this compound as IDE251.	NCT07540572
MEN2312	Menarini	Phase 1	ER-positive, HER2-negative advanced breast cancer, with elacestrantRecruiting. Discovered with Insilico Medicine. The two reports that describe the license disagree: the longevity review records a 550 million dollar deal in January 2025, the LongevityClaw assessment a January 2024 agreement of 12 million dollars upfront and more than 500 million in milestones.	NCT06638307
OP-3136	Olema Oncology	Phase 1	Advanced solid tumors, with palazestrantRecruiting. Thirty-two patients dosed as of November 2025, per the longevity review.	NCT06784193
SYH-2095	CSPC Pharmaceutical	Phase 1	Advanced solid tumorsEarly clinical. Retrieved from an internal record rather than a public registry identifier.	none retrieved
BAY-184	Bayer	Preclinical	Not yet definedNo registry record. Carried here because the longevity review lists it as investigational new drug stage; no trial record supports that.	none retrieved
Prelude KAT6A degrader	Prelude Therapeutics	Preclinical	Not yet definedNo registry record. Carried here because the longevity review lists it as investigational new drug stage; no trial record supports that. The review gives no compound code for it.	none retrieved

Sorted by stage, then by how many registry records each program has. The square marks the program that has reached the furthest stage. Where the sources say something about a program beyond its registry record, it is printed under the setting. Clinical evidence review, page 3

The record counts do not reconcile

The translation assessment reports eighteen records from its query and does not print them. This page can name nineteen: thirteen in the table above and six more for prifetrastat’s healthy-volunteer studies, listed below. Three of the programs in the table carry no registry identifier at all, so they cannot be among the eighteen either. Nothing in the pack says which records the query returned, so both totals are left as the reports give them rather than adjusted until they agree.

Clinical evidence review, page 1

Healthy-volunteer studies do not test a benefit in later life

Six healthy-volunteer clinical-pharmacology studies of prifetrastat were retrieved: NCT07117799, NCT07198035, NCT07636018, NCT07423286, NCT07335419 and NCT07731100.
These are pharmacokinetic, food-effect and drug-interaction studies within the oncology program. None of them is an aging study, and no report presents one as such. The two translation assessments disagree on how many there are: the short one lists all six, the long one names three.

Clinical evidence review, page 3

How far ahead the leader is

Pfizer’s PF-07248144 is the only program in Phase 3. The next furthest is Jiangsu Hengrui’s HRS-2189, in Phase 1 and 2. Roughly two or more years separate the leader from the rest of the field.

Translation assessment, page 4

The one trial with published numbers

Everything below comes from NCT04606446, Phase 1 and 2 dose escalation and expansion, reported in Mukohara et al., Nature Medicine 2024. It is the only place in this pack where a KAT6 inhibitor has been given to people and the results written up in a journal.

What the only published KAT6 inhibitor trial reported.
What was measured	What was found	What it means for a long-term program
Recommended dose	5 mg once daily with fulvestrant	The maximum tolerated dose was not reached, so the dose was set on other grounds.
Target engagement	More than 70 percent reduction in H3K23 acetylation, in tumor tissue and in blood cells	The mark the enzyme writes falls in patients as it falls in cells, and it falls in normal blood cells as well as in tumor tissue. That is target engagement, and it is the strongest single result in the pack. It is not evidence that the growth arrest seen in culture follows in a person.
Response rate, combination	30.2 percent in the published cohort of 43 patients; 37.2 percent in the later dose-optimization readout	The higher figure comes from a conference abstract, and its confidence interval is printed there with an unresolved upper bound, as 23.0 to 53.x.
Neutropenia	Grade 3 in 39.5 percent and grade 4 in 7.0 percent at the 5 mg dose; 59.8 percent at any grade across the whole Phase 1 population	Reversible and dose-dependent. Normal myeloid progenitors are affected at the dose that works. The two sets of figures are not two cuts of one group of patients: the 5 mg rates come from the dose-optimization readout, the any-grade rate from the published Phase 1.
Anemia	48.6 percent at any grade, 13.1 percent at grade 3 or 4	The second hematological signal, in the same direction.
Dysgeusia	About 83 percent, grade 1 and 2 only	Not dangerous. For a drug meant to be taken for years by well people, an 83 percent rate of altered taste is a discontinuation problem rather than a safety one.
Febrile neutropenia	None reported	The reason the neutropenia is described as manageable.

Figures as published. The response rate appears twice in the sources, at 30.2 percent in the journal paper and 37.2 percent in a later abstract; both are shown rather than the higher one alone. Translation assessment, page 1

The population these numbers came from

Everything in this table was measured in patients with metastatic breast cancer over months of treatment. The aging case needs years of treatment in people who are well. The trial cannot speak to that, and does not claim to.

Clinical evidence review, page 2

The expression ranking against the clinical record

The translation assessment took the indication ranking from the expression report and asked, for each entry, whether any clinical evidence exists.

Clinical evidence review, page 4

The differential-expression ranking set against what has actually been tested in people.
Indication	Size of the expression change	Significance as printed	Clinical evidence	Where that leaves it
Parkinson’s disease	0.370, Tier 1, both raised	p = 2.7e-07 for KAT6A, p = 0.001 for KAT6B	None	Expression only, not clinically validated
Alzheimer’s disease	0.327, Tier 1, both raised	p = 1.0e-14 for KAT6A, p = 2.8e-10 for KAT6B	None	Expression only, not clinically validated
Medulloblastoma	0.299, Tier 1, both raised	p = 1e-40 for KAT6B	No dedicated trial	Plausible in oncology, unproven
Invasive lobular carcinoma	0.230, Tier 1, both raised	—	Within the breast cancer program	Agrees with clinical reality
Acute myeloid leukemia and other blood cancers	Tier 2 and Tier 3	—	BeOne’s hematological study	Agrees with clinical reality
Idiopathic pulmonary fibrosis	0.151, Tier 2, both lowered	—	None	Low agreement
ER-positive, HER2-negative metastatic breast cancer	Not ranked at the top	—	Phase 3, with the only published efficacy data	The ranking placed the winner below several untested diseases

Expression values are the indication report’s, and the clinical column is the assessment’s. The number is that report’s own ranking figure: the average of the two genes’ fold changes with the direction set aside, so a disease where both genes fall can rank alongside one where both genes rise. Direction is given in words for that reason. Pulmonary fibrosis is the row where it matters: both genes are lower there, not higher. Clinical evidence review, page 4

The comparison the assessment insists on

A fold change of 0.3 to 0.4 in diseased tissue is not the same class of evidence as an amplification-driven dependency, and a ranking that treats them alike will put an untested disease above the one indication where the drug has already worked.

Clinical evidence review, page 4

The assessment sorts the candidate indications into three groups by what would have to be true for each to work.
Group	Indications	What would have to be true
Clinically anchored	ER-positive breast cancer, other hormone-driven tumors, acute myeloid leukemia	Nothing new. The mechanism is already engaged in patients and the readouts exist.
Adjacent, testable within oncology	Cancer interception in high-risk populations, senescence and secretory-phenotype modulation, myelodysplastic syndromes	Add geroscience measurements to trials that are running anyway.
Speculative for now	Parkinson’s disease, Alzheimer’s disease, idiopathic pulmonary fibrosis, healthy aging	Evidence that pushing the target in the intended direction changes the disease, which does not yet exist in any species.

Clinical evidence review, page 4

The assessment’s decision, taken separately for each program rather than for the target as a whole.
Program	Call	On what grounds
Oncology, hormone-driven breast cancer	Go	Human target engagement, a published response rate, a Phase 3 study running, and a manageable toxicity profile in this population.
Cancer interception and senescence biology, inside oncology trials	Conditional	Cheap to test, because the trials exist. Requires biomarker work rather than a new study.
Standalone aging or geroscience	No-go	No human evidence, no animal lifespan or healthspan experiment, a chronic-dosing safety profile that has not been established in well people, and an unresolved argument about whether the mechanism points in the right direction.

Clinical evidence review, page 5

Five things nobody has measured

Five things stand between the current evidence and an aging indication. The assessment lists them in the order they would have to be closed.

No non-oncology human data of any kind. Not a single registered or published trial in aging, neurodegeneration, fibrosis, or metabolic and vascular disease.
The direction of the senescence effect is unsettled. The mechanism induces senescence. Aging medicine spends its effort clearing senescent cells. Nobody has shown which effect dominates in a healthy older animal.
Chronic safety is unknown. Grade 3 neutropenia in roughly 40 percent of patients is acceptable in metastatic cancer. There is no evidence about what happens over years at a lower dose in someone who is well.
No validated aging endpoint has been measured. No epigenetic clock, no senescence panel, no functional healthspan measure has been recorded in anyone taking a KAT6 inhibitor.
The expression signal has not been tied to causation. A gene being raised in diseased tissue does not establish that lowering its activity helps. No genetic causal analysis has been run for either gene against any aging indication.

Clinical evidence review, page 5

How much weight the assessment puts on each of its own conclusions.
Claim	Confidence	On what basis
The oncology landscape as retrieved	High	Registry records and a peer-reviewed publication.
The updated response rate of 37.2 percent	Moderate	Conference abstract, with a confidence interval printed incompletely.
That there is no non-oncology human evidence	High	A negative across registry and literature retrieval, cross-checked against three curated aging databases in the longevity review.

Clinical evidence review, page 6

Design and risk

How the review would run it

Having argued that the pair belongs to aging biology, the longevity review sets out how it would run the program and what it expects to go wrong. That part of the review is reproduced here whole, because it is the part that stays useful whether or not a reader accepts the argument above it.

The severities are the review’s own. So is the reasoning in the last row, which is the clearest instance in the pack of a missing body of evidence being counted as an advantage.