Novartis 'compound 11' - 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 is not measured anywhere in the series
also called compound 11 · comp.11 · comp11
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 11 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 is not demonstrated anywhere in this series.** There is no compound 11 H3K79me2 arm in GSE149183, in either cell line, at any dose. Its inclusion as a DOT1L inhibitor rests entirely on the depositors' labelling and on its co-dosing at 100 nM with compound 10, whose engagement at that dose IS shown. Any claim resting on compound 11 alone inherits that gap. **What this project used it for.** Compound 11 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 **8 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 11' 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 | false |
| target engagement evidence | NONE - no H3K79me2 arm for this compound in this series, at any dose, in either cell line |
| men1 target peaks retained of 19 | 8 |
| dot1l target peaks retained of 5 | 5 |
| shown for fusion | KMT2A::MLLT3 in MOLM13 only - it is absent from the RS4;11 arm entirely |
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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 11? Without it, its use as the specificity control in a menin-versus-DOT1L comparison rests on the depositors' labelling alone.
- Is compound 11 target-engaging at 100 nM? It is the only arm in the head-to-head with no engagement control anywhere in the series, and it is also the arm with the weakest menin retention (8/19), so the one arm that could look like a counter-example is the one that cannot be verified.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Compound 11 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 11, 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 11 is dosed at 100 nM for 4 d in MOLM13 (per-sample GEO characteristics), alongside EPZ5676 at 1 microM in the H3K79me2 arm. No H3K79me2 arm exists for it.
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
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
In GSE149183, compound 11 at 100 nM leaves 8 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). Compound 11's MEN1 library is also the shallowest of the four MEN1 arms (12.44 M fragments, 89% of DMSO) and its 8/19 is within what that library recovers for peaks of matched strength anywhere in the genome (one-sided p = 0.6466, i.e. the matched expectation is slightly above 8), so the 8 is not a partial menin-eviction phenotype.
Evidence that argues against this (1)
- If compound 11 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
DOT1L methyltransferase inhibitor by depositor labelling; target engagement is not measured anywhere in the series
- analogous to →Pinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field
same class, same 100 nM dose as compound 10 in this deposit
compound 11 leaves menin on 8/19, which is exactly its own genome-wide rate for peaks of that strength (p = 0.6466)