The expansion of kinase drug discovery: new targets, platforms and indications.

Abstract

In the past 25 years, kinase drug discovery has grown into one of the most thriving areas in pharmaceutical research and development. What began as a field dominated by ATP-competitive small molecules has diversified into a broad therapeutic landscape that includes allosteric and covalent inhibitors, activators, proximity-induced modulators, targeted protein degraders and antibody-based therapies, with more than 150 regulatory approvals so far worldwide. In this Review, we provide a comprehensive analysis of the current kinase therapeutic landscape, including more than 2,100 kinase-targeting agents that have entered clinical development in more than 23,000 clinical trials. We cover drug platforms, new targeting approaches, the expanding target spectrum, approvals and clinical trends. Nearly half of the canonical human protein kinases have at least one clinical-stage agent, placing kinases among the most intensively explored drug target classes. Nevertheless, development remains highly concentrated around a small set of blockbuster kinase targets, such as EGFR. We also examine the features associated with successful kinase-targeting agents and causes of agent discontinuations and regulatory withdrawal.

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