Electrophilic Natural Products as Drug Discovery Tools

Electrophilic natural products (ENPs) are a rich source of bioactive molecules with tremendous therapeutic potential. While their synthetic complexity may hinder their direct use as therapeutics, they represent tools for elucidation of suitable molecular targets and serve as inspiration for the design of simplified synthetic counterparts. Here, we review the recent use of various activity-based protein profiling methods to uncover molecular targets of ENPs. Beyond target identification, these examples also showcase further development of synthetic ligands from natural product starting points. Two examples demonstrate how ENPs can progress the emerging fields of targeted protein degradation and molecular glues. Though challenges still remain in the synthesis of ENP-based probes, and in their synthetic simplification, their potential for discovery of novel mechanisms of action makes it well worth the effort.