Protein Kinase Inhibitors - Selectivity or Toxicity?

Abstract

Protein kinases are attractive therapeutic targets for various indications including cancer, cardiovascular, neurodegenerative and autoimmune diseases. This is due to the fact that they play key roles in the regulation of cell cycle, metabolism, cell adhesion, angiogenesis, regeneration and degeneration. Protein kinase families share a common catalytic core and hence usually display clear sequence and structural similarity. These sequence and structural similarities can lead to a lack of selectivity and off-target toxicity of drug candidates. The lack of selectivity can be beneficial but can also cause adverse toxicities which result in the discontinuation of promising drug candidates. The chapter reviews the challenges and common toxicities of protein kinase inhibitors and the latest advances in in-vitro and in-silico assays to screen for selectivity. The various methods for quantifying selectivity of kinase inhibitors and future directions including emerging more selective and safer kinase inhibitors have also been discussed.