Targeted covalent drugs of the kinase family.

In the past decade tremendous progress has been made toward a new class of therapeutics termed 'targeted covalent drugs', in which structure-based approaches are employed to create small molecules that inactivate their protein target through targeted covalent attachment to a specific cysteine. In the kinase field, this approach is demonstrating promise in overcoming the potency, selectivity, and efficacy challenges currently faced by reversible kinase inhibitors, with several advancing into late stage clinical testing. This design paradigm has been successfully applied to making drug candidates for epidermal growth factor receptor (EGFR), Her2, and Bruton's tyrosine kinase (Btk). Here we review recent pre-clinical and clinical advances with targeted covalent kinase inhibitors, and the potential for broader application of the approach. 2010 Elsevier Ltd. All rights reserved.