Novartis 'compound 10' - a DOT1L methyltransferase inhibitor from Perner et al. (Blood 2020), active at 100 nM, whose chemical structure is not given in the GEO deposit and whose target engagement at that dose IS demonstrated in the same series by a 5.6-fold spike-in-normalised H3K79me2 collapse by day 3
also called compound 10 · comp.10 · comp10
One of two new experimental drugs that block the DOT1L enzyme, made by Novartis and tested in this study. It works at a much lower dose than the older drug of the same kind.
The same thing, for a scientist
Compound 10 is one of two novel DOT1L inhibitors reported in Perner et al., *Blood* 2020;136(17):1983-1988, a collaboration between the Armstrong laboratory and Novartis Institutes for Biomedical Research; four authors are Novartis employees and shareholders [E1]. In GSE149183 it is used at **100 nM for 4 d** in MOLM13 for MEN1, DOT1L and H3K79me2 ChIP [E2]. **Potency, as asserted by the dosing rather than measured here.** The H3K79me2 arm of the same series doses EPZ5676 (pinometostat) at **1 microM** and compound 10 at **100 nM**, a ten-fold difference in the same experiment - the depositors' own statement about relative potency [E2]. **Target engagement at exactly this dose is demonstrated inside the series.** The depositors' dm6 spike-in table gives compound 10 at 100 nM in MOLM13 a ratio-to-DMSO of 5.57 at day 3, 17.93 at day 6 and 19.49 at day 9, with the fly read fraction rising from 1.69% to 9.43% [E2]. **This is the arm that carries the target-engagement control for the whole DOT1L-inhibitor class in this deposit**, because EPZ5676's H3K79me2 arm used a ten-fold higher dose than its factor ChIP and compound 11 has no H3K79me2 arm at all. **What this project used it for.** Compound 10 is one of the three DOT1L-inhibitor arms in the first side-by-side test of a menin inhibitor against DOT1L inhibitors on the MEN1 channel. It leaves **14 of 19** DMSO MEN1 peaks at canonical menin-MLL target loci in place and **5 of 5** DOT1L peaks, where VTP-50469 leaves none [E3]. **What is not known.** The structure, the ChEMBL identity, the selectivity panel and any independent replication. The GEO deposit names the compound only as 'compound 10' and the PubMed record carries no abstract; the Blood full text is not open access and was not retrieved. **This entry is deliberately thin and says so** rather than inferring properties from class membership.
Why an entry this thin is still worth writing
Two of the three DOT1L-inhibitor arms in this project's only menin-versus-DOT1L head-to-head are these compounds. Without entries they are invisible in the graph and the edges from the analysis nodes dangle, while the reader has no way to see how little is actually known about them. The granularity rule says one entry per thing; the honest version of that entry here is a short one that names the gaps.
| target | gene-dot1l |
|---|---|
| target interaction | DOT1L H3K79 methyltransferase catalytic activity |
| modality | small molecule |
| status | preclinical; reported 2020, no clinical development known to this project |
| originator | Novartis Institutes for Biomedical Research |
| structure disclosed in sources checked | false |
| concentration used in gse149183 NM | 100 |
| comparator dose in same series | EPZ5676 at 1 microM in the H3K79me2 arm |
| target engagement demonstrated | true |
| target engagement evidence | dm6 spike-in H3K79me2 ratio-to-DMSO 5.57 (d3), 17.93 (d6), 19.49 (d9) in MOLM13 at 100 nM |
| men1 target peaks retained of 19 | 14 |
| dot1l target peaks retained of 5 | 5 |
| shown for fusion | KMT2A::MLLT3 in MOLM13; KMT2A::AFF1 in RS4;11 for H3K79me2 only |
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- DOT1L is required for normal haematopoiesis and for normal B-lymphopoiesis, both recorded in this graph. A more potent DOT1L inhibitor raises the on-target marrow toxicity that limited the first generation rather than avoiding it.
- This compound is used here as a negative control for menin displacement. If it turned out to have any menin-interface activity, the central comparison in this beat would collapse - and nothing available to this project could detect that.
- What is the structure and the selectivity profile of compound 10? Without it, its use as the specificity control in a menin-versus-DOT1L comparison rests on the depositors' labelling alone.
- Does compound 10's potency advantage over pinometostat translate to an achievable exposure in vivo? Pinometostat failed clinically at achievable exposures, and a ten-fold more potent compound is the obvious way to retest that hypothesis.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Compound 10 is reported as a novel DOT1L inhibitor in Perner et al., Blood 2020;136(17):1983-1988, with Novartis co-authors.
Novel inhibitors of the histone methyltransferase DOT1L show potent antileukemic activity in patient-derived xenografts. · Perner F, Gadrey JY, Xiong Y, Hatton C, Eschle BK, Weiss A, Stauffer F, Gaul C, Tiedt R, Perry JA, Armstrong SA, Krivtsov AV · Blood 2020What this evidence cannot show
A brief report with no PubMed abstract and no open-access full text; the chemical structure was not retrieved. Four authors are Novartis employees and shareholders (declared conflict).
Evidence that argues against this (1)
- No independent laboratory has published on compound 10, and no selectivity panel is available to this project, so off-target activity cannot be excluded - including, in principle, activity at the menin-KMT2A interface, which would confound its use as the specificity control it is used as here. Perner F et al. 2020
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
In GSE149183 compound 10 is dosed at 100 nM for 4 d in MOLM13 (per-sample GEO characteristics), alongside EPZ5676 at 1 microM in the H3K79me2 arm. Its dm6 spike-in ratio-to-DMSO reaches 5.57 by day 3.
NCBI GEO GSE149183 - MEN1, DOT1L and H3K79me2 ChIP-seq in MOLM13 and RS4;11 under DMSO, VTP-50469, EPZ5676, compound 10 and compound 11; 31 samples, Homo sapiens; SubSeries of GSE149185, BioProject PRJNA627612, SRA SRP258055 · NCBI Gene Expression Omnibus 2020What this evidence cannot show
Nominal medium concentration, not measured intracellular exposure.
Evidence that argues against this (1)
- A ten-fold dose difference between two compounds in one experiment is the depositors' potency judgement, not a measured IC50, and no IC50 for either compound is available to this project. NCBI Gene Expression Omnibus 2020
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
In GSE149183, compound 10 at 100 nM leaves 14 of 19 DMSO MEN1 peaks and 5 of 5 DMSO DOT1L peaks at 15 pre-specified canonical menin-MLL target loci, where VTP-50469 at 50 nM leaves none of either.
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 2026What this evidence cannot show
n = 1 per condition, within-sample contrasts only, MOLM13 (KMT2A::MLLT3).
Evidence that argues against this (1)
- If compound 10 had unrecognised menin-interface activity, its retention of menin would be the surprising result rather than the expected one - but the direction of the observation is that it does NOT displace menin, which is the conservative outcome for a selectivity control. Oncofusion knowledge graph 2026
compound 10 at 100 nM gives a dm6 spike-in H3K79me2 ratio of 5.57 by day 3 - the target-engagement control for the whole DOT1L arm
DOT1L methyltransferase inhibitor, active at 100 nM, engagement shown by a 5.57-fold spike-in-normalised H3K79me2 collapse at day 3
- analogous to →Pinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field
same class; dosed at 100 nM in the series where pinometostat is dosed at 1 microM
compound 10 leaves menin on 14/19 target peaks at a demonstrably target-engaging dose - the arm that carries the class claim