molecules of the month

Con B-1

covalent inh. of remote ALK kinase cysteine

thought-provoking proposed MoA

from ceritinib and linker opt.

J. Med. Chem., Jan. 20, 2021

Sichuan University / Tsinghua University, CN

Chemical structure of molecule Con B-1 ALKi inhibitor
1 min read

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.

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