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J Am Chem Soc. 2013 Apr 10;135(14):5298-301. doi: 10.1021/ja401221b. Epub 2013 Mar 29.

Electrophilic fragment-based design of reversible covalent kinase inhibitors.

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1
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94158, USA.

Abstract

Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine thiols. Using this strategy, we identify electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated to afford 12 (RMM-46), a reversible covalent inhibitor that exhibits high ligand efficiency and selectivity for MSK/RSK-family kinases. At nanomolar concentrations, 12 blocked activation of cellular MSK and RSK, as well as downstream phosphorylation of the critical transcription factor, CREB.

PMID:
23540679
PMCID:
PMC3665406
DOI:
10.1021/ja401221b
[Indexed for MEDLINE]
Free PMC Article
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