molecules of the month

The academic covalent ALKi inhibitor, Con B-1, is thought-provoking initial proof-of-concept that remote kinase cysteines might be targetable from an active-site inhibitor. The authors show that a derivative of ceritinib with a remote electrophile attached can inhibit ceritinib more potently than a non-reactive control compound, that linker length significantly impacts activity, and that a 1:1 compound:ALK adduct can be detected on incubuation with an excess of reactive compound. The proposed MoA would be more convincing with an X-ray co-crystal structure rather than a docking model, or with a comparison to an appropriate Cys->Ala mutant, but it is worth considering this strategy in other contexts.