Kinase-targeting small-molecule inhibitors and emerging bifunctional molecules

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. Overview of the 72 FDA-approved small-molecule kinase inhibitors (SMKIs) classified by binding modes.The 72 SMKIs include a majority of type I and type II ATP-competitive inhibitors, four type III allosteric MEK inhibitors, one type IV allosteric ABL inhibitor, and eight covalent inhibitors.Proximity-inducing bifunctional molecules are emerging new chemical modalities that hold tremendous opportunities in kinase-targeting research.Kinase degradation occurs via PROTACs, stabilization via DUBTACs, phosphorylation via PHICS, and kinase dephosphorylation via PhoRCs.