Time to Get Turned on by Chemical Biology

The pressing need for innovation in drug discovery is spurring the emergence of drugs that turn on protein function, as opposed to shutting activity down. Several pharmacophores usher protein target gain-of-function, for instance: PROTACs promote protein target degradation; other drug candidates have been reported to function through dominant-negative inhibition of their target enzyme. Such classes of molecules are typically active at low target occupancy and display numerous advantages relative to canonical inhibitors, whose function is intrinsically tied to achieving, or exceeding a threshold occupancy. However, our ability to generally tap into gain-of-function processes through small molecule interventions is overall in its infancy. Herein, I outline how chemical biology is poised to help us bring this powerful idea to fruition. I further outline means through which gain-of-function events can be identified and harnessed.