Covalent targeting of acquired cysteines in cancer.

Covalent targeting of acquired cysteines in cancer.
Curr Opin Chem Biol. 2015 Nov 26;30:61-67
Authors: Visscher M, Arkin MR, Dansen TB
Abstract
The thiolate side chain of cysteine has a unique functionality that drug hunters and chemical biologists have begun to exploit. For example, targeting cysteine residues in the ATP-binding pockets of kinases with thiol-reactive molecules has afforded increased selectivity and potency to drugs like imbrutinib, which inhibits the oncogene BTK, and CO-1686 and AZD9291 that target oncogenic mutant EGFR. Recently, disulfide libraries and targeted GDP-mimetics have been used to selectively label the G12C oncogenic mutation in KRAS. We reasoned that other oncogenes contain mutations to cysteine, and thus screened the Catalog of Somatic Mutations in Cancer for frequently acquired cysteines. Here, we describe the most common mutations and discuss how these mutations could be potential targets for cysteine-directed personalized therapeutics.
PMID: 26629855 [PubMed - as supplied by publisher]

Source: Current Opinion in Chemical Biology - November 26, 2015 Category: Biochemistry Authors: Visscher M, Arkin MR, Dansen TB Tags: Curr Opin Chem Biol Source Type: research