M-808

M-808 covalently reacts with C329 of Menin via its acrylamide moiety and thereby inhibits the Menin-MLL protein-protein interaction. It is a very potent and efficacious inhibitor in vitro and in cells.

M-808 is developed by optimizing the earlier lead compound M-525, which is also very potent but is less selective over leukemia cells lacking the MLL fusion.

M-808 has not been checked for selectivity across a wider panel of common receptors and protein targets.

M-808 is administered IV in mice. There is no mentioning of alternative administration routes or other animal species in the original publication.

There is no DMPK data (in vitro/vivo) available.

Antiproliferative activity described at 2.8 µM for HL60 cells which do not carry a MLL fusion and therefore likely reflects off-target mediated effects. Therefore the probe should not be used at concentrations above 100 nM in cellular assays to keep a sufficient margin to these off-target effects of unknown origin. In general, no selectivity data have been published for this compound. As this is a covalent inhibitor data e.g. from a MS proteomics study would be needed to define the cellular interactome of this cmpd. Until those data are available I do not recommend to use this compound as a probe to study MLL/Menin biology in cells or animals

This compound may have clinical utility against MLLr leukemia. In contrast, more validation, in particular off-target effects of this compound, is needed before presenting this compound as a chemical probe to explore Mennin biology. The previous reported noncovalent compounds are better candidates as chemical probes of Mennin at this moment.