Irreversible inhibitors of c-Src kinase that target a nonconserved cysteine.

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Kwarcinski FE, Fox CC, Steffey ME, Soellner MB

Irreversible inhibitors of c-Src kinase that target a nonconserved cysteine.

ACS Chem Biol. 2012 Nov 16;7(11):1910-7. doi: 10.1021/cb300337u. Epub 2012 Sep 5.

PubMed ID

22928736 [ View in PubMed

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Abstract

We have developed the first irreversible inhibitors of wild-type c-Src kinase. We demonstrate that our irreversible inhibitors display improved potency and selectivity relative to that of their reversible counterparts. Our strategy involves modifying a promiscuous kinase inhibitor with an electrophile to generate covalent inhibitors of c-Src. We applied this methodology to two inhibitor scaffolds that exhibit increased cellular efficacy when rendered irreversible. In addition, we have demonstrated the utility of irreversible inhibitors in studying the conformation of an important loop in kinases that can control inhibitor selectivity and cause drug resistance. Together, we have developed a general and robust framework for generating selective irreversible inhibitors from reversible, promiscuous inhibitor scaffolds.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dasatinib	Tyrosine-protein kinase CSK	Protein	Humans	Unknown	Inhibitor	Details