Kinase-targeting small-molecule inhibitors and emerging bifunctional molecules

Abstract

Kinases are among the most successful drug targets. To date, 72 small-molecule kinase inhibitors (SMKIs) have been approved by the US FDA, together with ~500 SMKIs in clinical trials. Although the topic has been heavily reviewed in recent years, an overview that focused on the currently approved SMKIs in combination with the emerging kinase-targeting bifunctional molecules is absent. Herein, we first provide an updated overview of the approved SMKIs, with an emphasis on their binding modes, classified in groups of type I and II ATP-competitive inhibitors, type III and IV allosteric inhibitors, and covalent inhibitors. We then highlight the novel chemical modalities in kinase targeting by using different types of proximity-inducing bifunctional molecules for kinase degradation and modifications.

Keywords: allosteric inhibitor; covalent inhibitor; kinase inhibitor; proteolysis targeting chimera (PROTAC); proximity-inducing bifunctional molecule; small molecule.