Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.

Autor: Hall A; UCB, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium., Abendroth J; UCB Seattle, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States., Bolejack MJ; UCB Seattle, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States., Ceska T; UCB, 216 Bath Road, Slough SL1 3WE, U.K., Dell'Aiera S; UCB, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium., Ellis V; UCB, 216 Bath Road, Slough SL1 3WE, U.K., Fox D 3rd; UCB Seattle, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States., François C; NovAliX, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium., Muruthi MM; UCB Seattle, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States., Prével C; UCB, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium., Poullennec K; UCB, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium., Romanov S; NANOSYN, 3100 Central Expressway, Santa Clara, California 95051, United States., Valade A; UCB, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium., Vanbellinghen A; UCB, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium., Yano J; UCB Boston, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Geraerts M; UCB, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2022 Jun 25; Vol. 13 (7), pp. 1099-1108. Date of Electronic Publication: 2022 Jun 25 (Print Publication: 2022).
DOI: 10.1021/acsmedchemlett.2c00134
Abstrakt: We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an S N Ar reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by in vitro biochemical experiments and was confirmed by mass spectrometry. Ultimately, the displacement of the 2-chloro moiety was confirmed by crystallization of an inhibitor with the CTKD. We also disclose the crystal structures of three compounds from this series bound to the CTKD of MSK1, in addition to the crystal structures of two unrelated RSK2 covalent inhibitors bound to the CTKD of MSK1.
Competing Interests: The authors declare the following competing financial interest(s): Some of the authors may hold stock, stock awards, or stock options in the companies which employ them.
(© 2022 American Chemical Society.)
Databáze: MEDLINE
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