Time to Get Turned on by Chemical Biology

Abstract

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.

A Primer on Harnessing Non-enzymatic Posttranslational Modifications for Drug Design

“…We therefore believe that we have provided good evidence that biological activity can be modulated in a DN fashion through specific covalent engagement with a specific electrophile. 67 If this engagement be ushered through a ligandable interaction, even if that ligandable interaction should lead to measurable effects on the target protein, the covalent handle can exert its effects in a manner predictable based on data derived from studying protein-specific electrophile labeling. Using T-REX or other strategies that may arise to model protein specific electrophile engagement we can hone our resources to focus on the most responsive target proteins, and interrogate off-target effects in ways that were not previously possible.…”

Hitting the Bullseye: Endogenous Electrophiles Show Remarkable Nuance in Signaling Regulation

“…Indeed, each electrophile sensitive protein identified offers access to (context-dependent) target modulation. This can be either inhibitory, or stimulatory, or potentially gain of function . We have identified proteins that sense electrophiles through T-REX but do not seem to respond functionally to electrophiles. , For the time being, these appear to be proteins that are only capable of achieving very low occupancy under standard T-REX methods.…”

Hitting the Bullseye: Endogenous Electrophiles Show Remarkable Nuance in Signaling Regulation

“…Indeed, each electrophile sensitive protein identified offers access to (context-dependent) target modulation. This can be either inhibitory, or stimulatory, or potentially gain of function 72 . We have identified proteins that sense electrophiles through T-REX TM but do not seem to respond functionally to electrophiles 73 .…”