Bounded failure: 'menin inhibitor-resistant cells' is a drug entry's central claim and neither the paper nor any repository defines it
also called PMID 41685902 bounded failure · DOT1L808 resistant cell identity · DOT1L degrader system
A drug entry in this graph says a DOT1L degrader works in cells resistant to menin inhibitors. Nobody has said what made those cells resistant, and the paper is unreadable with no deposited data - so the graph cannot tell whether the finding would apply to a real resistant patient.
The same thing, for a scientist
`drug-dot1l808` carries the caveat *"The E3 ligase, linker, selectivity panel and pharmacokinetics are not stated in the abstract, and 'menin inhibitor-resistant cells' is not defined there - resistance route matters, since a MEN1 binding-site mutation and a lineage switch would predict very different cross-resistance"* [E1]. The caveat is exactly right and this beat could not close it. No route returns anything: no PMCID in PubMed esummary or the Europe PMC core record, `isOpenAccess: N`, `inEPMC: N`, zero GEO by elink, zero SRA/BioSample/BioProject, and a GEO keyword search on `DOT1L AND degrader` returns four series - three from an ENL degrader study and one on mutant NPM1 chromatin binding - none of which is this paper [E2]. **Why this one is worse than an ordinary unresolved provenance question.** *Menin inhibitor-resistant* is not a system description, it is a **derived phenotype**, and the derivation is the whole content of the claim. Cells made resistant by a MEN1 binding-site mutation (M327I and the rest of that class) retain fusion-driven transcription and would be expected to stay DOT1L-dependent. Cells resistant by lineage switch, by loss of the fusion's target programme, or by a UTX/complex switch of the kind recorded in `ana-unstated-system-menin-utx-switch-resolved` would not. A degrader that rescues the first tells you something narrow and real; one that rescues the second tells you something much larger. **The abstract's phrase is compatible with both and the graph cannot distinguish them** [E3].
What a resistance model needs to state, and what is missing
| Needed | Available |
|---|---|
| Parental line and its fusion | not stated |
| How resistance was generated (mutagenesis, chronic exposure, engineered) | not stated |
| The resistance lesion (MEN1 mutation? which residue? expression change? lineage switch?) | not stated |
| Which menin inhibitor the cells are resistant to | not stated |
| Cross-resistance panel | not stated |
| E3 ligase, linker, degradation selectivity | not stated |
Every row is a routine Methods fact and none is recoverable. A degrader entry in this graph therefore records an intervention whose claimed advantage - activity where menin inhibitors fail - rests on an undefined comparator.
This is the beat's clearest case of a caveat that should block an entry's confidence rather than annotate it. drug-dot1l808 should carry confidence_overall no higher than weak on the resistance claim until the resistance route is known.
The 2026 cluster
Four of this beat's eight bounded failures are 2026 papers: this one, ana-unstated-system-igf2bp3-t411-unresolved, the USP22 paper (which did resolve, but only because its authors deposited), and the DOT1L B-cell paper (which resolved the same way). The pattern is that recent subscription articles are unreadable and their depositions, when they exist, are the only public record of what was done.
That has a practical consequence for how this project should triage. For a 2026 paper behind a paywall, the deposition is not a fallback - it is the primary and often sole source, and its presence or absence determines whether the citation can be used at all. Of the four recent papers here, two deposited and resolved completely, and two deposited nothing and resolved not at all. There is no middle outcome.
| script | none - Europe PMC, NCBI elink, GEO keyword search |
|---|---|
| status | run |
| result summary | Unresolved. No PMCID, no deposition, no readable text. The central undefined term is a derived phenotype ('menin inhibitor-resistant cells') rather than a cell system, and the derivation determines whether the drug entry's claim is narrow or broad. |
| what would resolve it | Subscription access to J Med Chem 2026, specifically the resistance-model description in the Methods and the supporting information for the E3 ligase and linker. |
| resolution class | bounded failure |
| recommended action | lower drug-dot1l808's confidence on the menin-resistance claim to weak until the resistance route is known |
inputs
[ "PMID 41685902" ]
routes tried
[ "PubMed esummary (no pmc)", "Europe PMC core (pmcid null, isOpenAccess N, inEPMC N)", "elink pubmed->gds, sra, biosample, bioproject (0 each)", "esearch db=gds 'DOT1L AND degrader' (4 series, all excluded by title and Series_pubmed_id)" ]
entries affected
[ "drug-dot1l808" ]
- A degrader removes DOT1L protein and therefore its scaffolding functions as well as its catalysis, so normal-tissue toxicity should be expected to exceed that of catalytic DOT1L inhibitors, whose clinical experience already showed a narrow window.
- If the resistant cells were made resistant by chronic exposure in culture, their lesion may be a culture artefact with no patient counterpart, and a clinical programme built on it would have no eligible population.
- Proposing a DOT1L degrader for post-menin-inhibitor relapse assumes DOT1L dependence persists after menin-inhibitor failure; the one resistance mechanism this graph has resolved in detail predicts a complex switch, which is precisely the setting in which that assumption is least safe.
- By what route were the menin inhibitor-resistant cells made resistant? This single fact decides whether the degrader's claimed advantage is narrow or general.
- Does DOT1L dependence survive a UTX-dependent complex switch? If it does not, a DOT1L degrader would fail in exactly the resistance setting it is being proposed for.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
The DOT1L degrader paper reports the development of DOT1L-targeted protein degraders for treating MLL-rearranged leukaemia, and its abstract does not define what makes its menin inhibitor-resistant cells resistant, nor state the E3 ligase, linker, selectivity panel or pharmacokinetics.
Development of DOT1L-Targeted Protein Degraders for Treating MLL-r Leukemia. · Quan S, Unno K, Gupta DG, Yang W, Guo Q, Dufficy MF, Kerber MM, Elmashae AA, Pan H, Zhu JL, Schiltz GE, Abdulkadir SA · J Med Chem 2026What this evidence cannot show
Identifiers taken from the NCBI esummary record fetched on 2026-09-19. This entry asserts nothing about the degrader's chemistry or the resistance model, and deliberately does not guess either.
Evidence that argues against this (1)
- A DOT1L degrader would be expected to outperform a catalytic DOT1L inhibitor on scaffolding functions rather than on menin-inhibitor cross-resistance specifically, so the resistance framing may be a marketing of the result rather than its mechanism - which only the undisclosed resistance model could settle. Wu F et al. 2021
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
No full text or deposition is reachable: PubMed esummary returns no PMC identifier, the Europe PMC core record returns pmcid null with isOpenAccess N and inEPMC N, elink from the PMID to GEO, SRA, BioSample and BioProject returns zero records, and a GEO keyword search on 'DOT1L AND degrader' returns four series belonging to an ENL degrader study and a mutant-NPM1 study rather than to this paper.
Europe PMC REST core record, NCBI elink and GEO keyword search for PMID 41685902 · Europe PMC and NCBI Entrez Programming Utilities 2026What this evidence cannot show
Run on 2026-09-19 from a single network location without subscription access. A medicinal-chemistry paper in J Med Chem would not normally deposit sequencing, so the GEO negative is expected and uninformative; the informative negative is the absence of any readable text. The four keyword hits were excluded by title, following the attribution rule this beat established after the GSE200059 near-miss.
Evidence that argues against this (1)
- Medicinal-chemistry papers deposit compound characterisation to supporting-information PDFs rather than to repositories, so the chemistry half of this caveat - E3 ligase, linker, selectivity - is recoverable from the paper and unreachable from any database by construction. Morgan M et al. 2022
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin-inhibitor resistance arises by mechanistically distinct routes with different predicted DOT1L dependence, including MEN1 binding-site mutation and a UTX-dependent switch between mammalian MLL complexes, so the undefined phrase 'menin inhibitor-resistant cells' is compatible with resistance models that would and would not remain DOT1L-dependent.
A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin-MLL Inhibition. · Soto-Feliciano YM, Sánchez-Rivera FJ, Perner F, Barrows DW, Kastenhuber ER, Ho YJ, Carroll T, Xiong Y, Anand D, Soshnev AA, Gates L, Beytagh MC, Cheon D, Gu S, Liu XS, Krivtsov AV, Meneses M, de Stanchina E, Stone RM, Armstrong SA, Lowe SW, Allis CD · Cancer Discov 2023What this evidence cannot show
The cited paper establishes the complex-switch route and its own systems were resolved elsewhere in this beat as murine and human myeloid MLL-AF9 plus an NPM1c line; it is cited here for the existence of mechanistically distinct resistance routes, not for their frequency. MEN1 binding-site mutations are recorded elsewhere in this graph and are not re-cited here.
Evidence that argues against this (1)
- If DOT1L dependence survives every known menin-resistance route, the distinction this entry insists on would be moot - but that is a claim nobody has tested across routes, and assuming it is precisely the shortcut the caveat was written to prevent. Neville D et al. 2026
the resistance route behind this drug's central claim is undefined and unrecoverable
the one resolved menin-resistance mechanism predicts the setting where a DOT1L degrader would fail
a degrader removes DOT1L scaffolding as well as catalysis
bounded failure in the unstated-system worklist