M-808 — a covalent menin-MLL inhibitor with a co-crystal, five years before the graph noticed it
also called M-808 · compound 16
M-808 is a laboratory compound that sticks permanently to menin rather than binding and letting go. It shrank tumours in mice and was never developed.
The same thing, for a scientist
Structure-based optimisation of a covalent menin-inhibitor series produced M-808: inhibition of leukaemia cell growth at **low nanomolar** concentrations, **partial tumour regression in an MV4;11 xenograft** at a well-tolerated schedule, and a **co-crystal structure with menin** giving the structural basis for the covalent interaction. It is a tool compound that was offered for further optimisation, and this graph — which holds a phase-2 druggability dossier reasoning about menin's structural and chemical matter — had no record of it or of its laboratory.
Why a 2020 tool compound is worth an entry now
This graph treats covalent menin inhibition as one compound's quirk. drug-icovamenib describes BMF-219 as the covalent menin inhibitor and records that its oncology programme was terminated — for strategic rather than safety or efficacy reasons — leaving the impression of a dead end reached once.
M-808 shows there is a medicinal-chemistry lineage behind it with published structural basis and in vivo activity. That matters for the phase-2 dossier, which reasons about menin's chemical matter by counting ChEMBL rows, and it matters more for the class question: the graph reasons about five menin inhibitors as one intervention, and covalent-versus-reversible is the most obvious axis on which that could fail.
| target | gene-men1 |
|---|
- A covalent inhibitor's exposure is governed by protein resynthesis rather than by plasma half-life, so off-target modification accumulates with repeated dosing in a way reversible occupancy does not.
- Menin is a tumour suppressor whose germline loss causes multiple endocrine neoplasia type 1. Permanent inactivation of a tumour suppressor is a different risk profile from transient occupancy, and this graph's endocrine beat has already had to separate germline penetrance over decades from weeks of partial pharmacological inhibition.
- The same pocket binds JUND with the opposite transcriptional effect; a covalent agent removes that occupancy for the protein's lifetime.
- No paediatric or infant data exist for any covalent menin inhibitor, and the one that reached patients had its oncology programme terminated.
- Which residue does M-808 modify, and is it conserved in the MEN1 interface mutants that confer clinical resistance to reversible inhibitors?
- Did the series stop for a published reason, or is its absence from the clinic simply unreported?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Structure-based optimisation of a class of covalent menin inhibitors produced M-808, which inhibits leukaemia cell growth at low nanomolar concentrations and achieves partial tumour regression in an MV4;11 xenograft model at a well-tolerated dose schedule; a co-crystal structure of M-808 in complex with menin provides the structural basis for the high-affinity covalent interaction.
Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong In Vivo Antitumor Activity · Journal of Medicinal Chemistry 2020What this evidence cannot show
Abstract read; full text not read, so the modified residue, the warhead chemistry and the selectivity data are not established here. MV4;11 is a KMT2A::AFF1 myelomonocytic line — the right fusion and the wrong lineage for infant B-ALL. 'Partial regression' is the authors' own word and is weaker than the complete responses degrader and combination programmes now report.
Evidence that argues against this (2)
- A 2020 tool compound offered 'for further optimisation' that has not entered clinical development in the five years since is, on the base rate, a compound someone decided not to take forward. The entry records what was published and not why the series stopped, and absence of a successor is weak evidence about the modality. Oncofusion knowledge graph (internal analysis) 2026
- Covalency against menin has a specific liability the abstract does not address: menin binds JUND in the same central pocket with the opposite transcriptional effect, so a permanent modification removes both occupancies for the protein's lifetime rather than shifting an equilibrium. Whatever JUND displacement contributes, a covalent agent commits to it. Nature 2012