M-808

Covalent Inhibitor of MEN1

Structure

Information

Protein target names: MEN1

Mechanism of action: Covalent Inhibitor

Recommended in-cell concentration:
10-40 nM

In Vitro Validations

Uniprot ID: O00255
Target Class: Epigenetic
Target SubClass: Scaffold Protein
Potency: IC50
Potency Value: 2.6 nM
Potency Assay: FP assay
PDB ID for probe-target interaction (3D structure): 6WNH
Structure-activity relationship: yes
Target aliases:
Menin, SCG2, MEN1, MEN1_HUMAN

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 7 Jul 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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

(last updated: 11 Jul 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 24 Sept 2020 )