title: Covalent targeting of acquired cysteines in cancer.
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.
authors.affiliation: Center for Molecular Medicine, Molecular Cancer Research, University Medical Center Utrecht, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Visscher
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA. Electronic address: Michelle.arkin@ucsf.edu.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.affiliation: Center for Molecular Medicine, Molecular Cancer Research, University Medical Center Utrecht, The Netherlands. Electronic address: t.b.dansen@umcutrecht.nl.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Dansen
mesh_terms: D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D057285:Precision Medicine; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D003545:Cysteine