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Targeting the Non-Catalytic Functions: a New Paradigm for Kinase Drug Discovery?

Protein kinases have been highly fruitful targets for cancer drug discovery in the past two decades, while most of these drugs bind to the "adenosine triphosphate (ATP)-site" and inhibit kinase catalytic activity. Recently, accumulated evidence suggests that kinases possess functions beyond catalysis through their scaffolds, and the scaffolding functions could play critical roles in multiple cellular signaling and cell fate controls. Small molecules modulating the noncatalytic functions of kinases are rarely reported but emerge as new promising therapeutic strategies for various diseases. Herein, we summarize the characterized noncatalytic functions of kinases, and highlight the recent progress on developing small-molecule modulators of the noncatalytic functions of kinases. Mechanisms and characteristics of different kinds of modulators are also discussed. It is also speculated that targeting the noncatalytic functions would represent a new direction for kinase-based drug discovery.