DrugstrongQ136-menin-vs-dot1l-inhibitors

VTP-50469 - the preclinical menin-KMT2A interface inhibitor that almost every chromatin experiment in this field actually used, and which had no entry of its own in this graph

also called VTP50469 · VTP 50469

This is the laboratory version of the menin-blocking drug. Nearly every experiment people cite about what menin inhibitors do to chromatin was done with this compound, not with the approved medicine.

The same thing, for a scientist

VTP-50469 is a potent, orally bioavailable small-molecule inhibitor of the menin-KMT2A protein-protein interface, from Vitae/Allergan, and the compound used in the pivotal preclinical chromatin and PDX study [E1]. **It is the tool compound behind essentially every menin-inhibitor chromatin measurement this project reasons about** - GSE127507/GSE127508, GSE260742 and GSE149183 all use VTP-50469, not revumenib. **Why it needed its own entry.** This graph holds `drug-revumenib` (SNDX-5613), the clinical and now FDA-approved compound, and treats VTP-50469 throughout as 'the preclinical analogue of revumenib'. **They are different molecules**, and the distinction is load-bearing: no entry in this corpus establishes that the two produce the same chromatin readout, and every deposited occupancy measurement is the tool compound's. **What it does to chromatin, from the pivotal report** [E1]: global loss of menin binding in human KMT2A-rearranged lines at 3 d; MLL1 **not** globally displaced, with locus-restricted loss at MEIS1, MEF2C and JMJD1C and retention at the HOXA cluster, MYB and GAPDH; the pattern reproduced by genetic MEN1 knockout. **Added by this beat** [E2]: at **50 nM for 4 d in MOLM13**, VTP-50469 leaves **zero of 19** DMSO MEN1 peaks at 15 canonical target loci (strength-matched permutation p = 0.0003) and zero of 5 DMSO DOT1L peaks, while three DOT1L inhibitors at twice the concentration leave most of them. That is the first side-by-side demonstration that menin displacement is drug-class specific. **Registry status.** `VTP-50469` and `VTP50469` were both queried against ChEMBL by name and **both return zero compounds** (hyphenated and unhyphenated are different strings and both were tried) [E3]. So no ChEMBL id, structure, or calculated properties are recorded here - that is a genuine absence, not an omission.

Go deeper

The substitution nobody has tested

Claims of the form 'menin inhibitors do X to chromatin' in this corpus are almost always 'VTP-50469 does X to chromatin'. Revumenib is a different spirocyclic chemotype with a different exposure profile, and the corpus contains no experiment comparing the two compounds' chromatin effects head to head. Until one exists, the substitution should be written as an assumption wherever it is made.

Facts and figures

target	gene-men1
target interaction	menin-KMT2A (MBM1) protein-protein interface
modality	small molecule (oral, reversible PPI inhibitor)
status	preclinical tool compound; not clinically developed. Its clinical successor in this graph is drug-revumenib (SNDX-5613).
originator	Vitae Pharmaceuticals / Allergan
chembl query result	0 compounds for 'VTP-50469' and 0 for 'VTP50469' in ChEMBL v34
chromatin effect	global loss of menin binding; MLL1 not globally displaced; in GSE149183, complete loss of MEN1 and DOT1L peak calls at 15 canonical target loci
shown for fusion	KMT2A::MLLT3 (MOLM13, murine MLL-AF9), KMT2A::AFF1 (RS4;11, in GSE127507 only), KMT2A::AFDN (ML-2)

trials

[]

deposits using it

[
  "GSE127507 / GSE127508 (RS4;11, MOLM13, ML-2; 3 d)",
  "GSE260742 (murine MLL-AF9; 500 nM)",
  "GSE149183 (MOLM13; 50 nM, 4 d; MEN1 and DOT1L ChIP)"
]

concentrations used in those deposits

{
  "GSE260742": "500 nM",
  "GSE149183": "50 nM (per-sample field); the shared protocol text says 100-330 nM"
}

key ae

[]

resistance

[
  "MEN1 pocket mutations (M327I and relatives) reported for the clinical menin-inhibitor class"
]

How this could bite us back

A tool compound used at 50-500 nM in culture tells you little about what an approved drug achieves at clinical trough. The chromatin phenotypes this project treats as established for 'menin inhibition' are established for one preclinical compound at saturating concentrations.
Because VTP-50469 has no ChEMBL record, no off-target or selectivity panel is reachable from this graph for the compound behind most of its mechanistic evidence. An off-target effect would look exactly like the on-target chromatin result reported here.

Still open

Do VTP-50469 and revumenib produce the same chromatin readout at matched target occupancy? Every occupancy claim this project makes about 'menin inhibitors' rests on the tool compound, and no head-to-head chromatin comparison exists.
What is VTP-50469's structure and ChEMBL identity? It is absent from ChEMBL under both spellings, which means no automated property, selectivity or off-target lookup in this project can reach the compound its evidence base is built on.

Every source behind this entry (3)

E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
VTP-50469 is a menin-KMT2A interface inhibitor that induces global loss of menin binding in human KMT2A-rearranged leukaemia lines without globally displacing MLL1, and eradicates disease in PDX models of MLL-rearranged leukaemia.
A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia. · Krivtsov AV, Evans K, Gadrey JY, et al. · Cancer Cell 2019
PMID 31821784 DOI
What this evidence cannot show
Preclinical only; the compound did not itself go into patients. Cell lines and PDX, 3 d for the chromatin work.
Evidence that argues against this (1)
- The same paper reports MLL1 retained at HOXA and MYB under VTP-50469, so 'the drug removes the fusion from its targets' is NOT what it shows and should not be attributed to it. Krivtsov AV et al. 2019
E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
In GSE149183 (MOLM13, 50 nM, 4 d, hg38) VTP-50469 leaves 0/19 DMSO MEN1 peaks and 0/5 DMSO DOT1L peaks at 15 pre-specified canonical menin-MLL target loci, against 14/19, 14/19 and 8/19 (MEN1) for EPZ5676, compound 10 and compound 11 at 100 nM.
analyses/menin-inhibitor-against-dot1l-inhibitors-in-one-deposit (PREREGISTRATION.md, run.py, results.json) - this repository, re-analysis of the ten deposited GSE149183 MACS2 peak tables · Oncofusion knowledge graph 2026
What this evidence cannot show
n = 1 per condition, within-sample contrasts only (no spike-in on these ChIPs), KMT2A::MLLT3 only. The deposit's own metadata gives conflicting concentrations for VTP-50469 - 50 nM in the per-sample field, 100-330 nM in the shared protocol text.
Evidence that argues against this (1)
- A menin-pocket inhibitor could mask the epitope of the anti-menin antibody rather than evict menin. No orthogonal (tagged or second-epitope) readout exists in any deposit this project has found, so eviction and masking are not separated anywhere. Oncofusion knowledge graph 2026
E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Neither 'VTP-50469' nor 'VTP50469' returns any compound in ChEMBL v34 by name search, so no ChEMBL identifier or calculated property set is available for this compound.
ChEMBL v34 compound name search for VTP-50469 and VTP50469 - 0 compounds returned for each · EMBL-EBI ChEMBL 2026
What this evidence cannot show
Bounded to a name/synonym search in ChEMBL v34. A structure search was not run because no SMILES for VTP-50469 was in hand, and the compound may be present under a depositor code or its parent patent identifier rather than the VTP name.
Evidence that argues against this (1)
- Absence from ChEMBL is absence from one registry, not evidence that the structure is undisclosed - it is described in the Krivtsov et al. supplementary material and in Vitae patent literature, neither of which was fetched here. Krivtsov AV et al. 2019

Connected to

← related toSearching 32 GEO series and 2,312 samples for a menin readout under DOT1L inhibition: exactly ONE distinct experiment exists, MOLM13_MEN1-ChIP_EPZ5676_4d at 100 nM, and it is the sample Q136 already used - so the deflationary reading of Q136 is blocked not by a missing assay but by a ~50-fold DOSE GAP, and Q136's drug-class conclusion rests on a single unreplicated sample in a single cell line
the only public menin readout under a DOT1L inhibitor is at 100 nM EPZ5676, ~50-fold below the exposures the MLL1-channel comparison uses
← related toA full 2x2 on the MLL1 channel in one run - DMSO, EPZ5676 1 uM, VTP-50469 100 nM and both - closes cycle 83's thirty-cycle-old threat: at the fusion's strongest MLL1 sites the menin inhibitor removes 58.3% against the DOT1L inhibitor's 17.5%, a 3.33-fold separation at TEN TIMES the DOT1L dose Q136 could test, with sequencing depth running opposite to the effect in every arm
at 100 nM it removes 58.3% of the fusion's strongest MLL1 sites against EPZ5676 1 uM's 17.5%
← related toThe menin inhibitor in this head-to-head is at 50 nM and all three DOT1L inhibitors are at 100 nM - the comparison is dose-biased AGAINST the menin inhibitor - and compound 10's target engagement at exactly 100 nM is demonstrated inside the same series by a spike-in-normalised H3K79me2 collapse of 5.6-fold by day 3
VTP-50469 dosed at 50 nM in the factor-ChIP arm, with a conflicting 100-330 nM in the deposit's shared protocol text
← related toA tempting second finding that does NOT survive its control: about half of each treated sample's peaks are absent from DMSO, but the two independent VTP-50469 libraries share only 10.5% of their gained sites - against 7.7%, 8.1% and 10.6% for the DOT1L-inhibitor arms - so the gained peaks are threshold noise and there is no evidence of redistribution
no VTP-50469-specific gained-site programme: 10.5% concordance against controls of 7.7-10.6%
inhibits →MEN1 / menin — the adaptor the fusion cannot work without
menin-KMT2A (MBM1) protein-protein interface inhibitor
analogous to →Revumenib (SNDX-5613, Revuforj) — first approved menin–KMT2A interface inhibitor
the preclinical tool compound behind nearly every chromatin claim attributed to the clinical drug - and no head-to-head chromatin comparison exists
treated by →KMT2A::MLLT3 (MLL-AF9), t(9;11)(p21.3;q23.3)
used at 50 nM for 4 d in MOLM13 in GSE149183
← testsFirst deposit to put both drug classes on the MEN1 channel in one experiment: VTP-50469 leaves ZERO of the 19 DMSO menin peaks at 15 canonical menin-MLL target loci, while EPZ5676 keeps 14, compound 10 keeps 14 and compound 11 keeps 8 - strength-matched permutation p = 0.0003, and the zero is unchanged at every flank from 0 to 100 kb
VTP-50469 at 50 nM leaves 0/19
← testsIn SEM, the infant-derived KMT2A::AFF1 line, VTP-50469 lowers H3K4me3 at menin-bound sites by 23% relative to H3K4me3-matched menin-free sites (95% CI 13-33%), while the DOT1L inhibitor EPZ-5676 changes it by 1% (CI -4 to +6%)
Measures VTP-50469's effect on H3K4me3 at menin-bound sites in the infant-derived index-fusion line
← related toBounded absence: in GSE159608's SEM line, VTP-50469 was profiled for H3K4me3 only - no menin, no H3K27ac, no H3K79me2, no RNAP2 and no IgG under the drug - and no library in the series carries a spike-in normalisation, so an absolute change in any mark is unmeasurable here
Bounds what the only deposited menin-inhibitor chromatin arm in this line can measure
← related toIn SEM, H3K4me3 responds to menin displacement the way a partially redundant mark should: selectively at menin-bound sites, by about a quarter, and not at all under a DOT1L inhibitor - which bounds how much of a menin inhibitor's lethality H3K4me3 can be carrying
Bounds how much of the drug's action H3K4me3 can be transmitting
← testsExperiment: spike-in-normalised H3K4me3, menin and IgG CUT&Tag in SEM under VTP-50469 and EPZ-5676 - the one missing experiment that turns every ratio in this beat into an absolute number
Measures menin eviction and H3K4me3 in the same cells under VTP-50469
← testsExperiment: a 6 / 24 / 72 hour / 7 day VTP-50469 time course in SEM reading menin occupancy and H3K4me3 together, to decide whether the 23% is a partial effect or a slow one
A 6 h to 7 d exposure series in SEM