2. Academic Validation
  3. Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1

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

  • ACS Med Chem Lett. 2022 Jun 25;13(7):1099-1108. doi: 10.1021/acsmedchemlett.2c00134.
Adrian Hall 1,  Jan Abendroth 2,  Madison J Bolejack 2,  Tom Ceska 3,  Sylvie Dell'Aiera 1,  Victoria Ellis 3,  David Fox 3rd 2,  Cyril François 4,  Muigai M Muruthi 2,  Camille Prével 1,  Karine Poullennec 1,  Sergei Romanov 5,  Anne Valade 1,  Alain Vanbellinghen 1,  Jason Yano 6,  Martine Geraerts 1
Affiliations

Affiliations

  • 1 UCB, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium.
  • 2 UCB Seattle, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States.
  • 3 UCB, 216 Bath Road, Slough SL1 3WE, U.K.
  • 4 NovAliX, Avenue de l'Industrie, Braine-L'Alleud 1420, Belgium.
  • 5 NANOSYN, 3100 Central Expressway, Santa Clara, California 95051, United States.
  • 6 UCB Boston, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
PMID: 35859861 DOI: 10.1021/acsmedchemlett.2c00134
Abstract

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 SNAr 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.

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