Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Targeted protein degradation (TPD), a promising therapeutic
strategy
in drug discovery, has great potential to regulate the endogenous
degradation of undruggable targets with small molecules. As vital
resources that provide diverse structural templates for drug discovery,
natural products (NPs) are a rising and robust arsenal for the development
of therapeutic TPD. The first proof-of-concept study of proteolysis-targeting
chimeras (PROTACs) was a natural polyketide ovalicin-derived degrader;
since then, NPs have shown great potential to promote TPD technology.
The use of NP-inspired targeted protein degraders has been confirmed
to be a promising strategy to treat many human conditions, including
cancer, inflammation, and nonalcoholic fatty liver disease. Nevertheless,
the development of NP-inspired degraders is challenging, and the field
is currently in its infancy. In this review, we summarize the bioactivities
and mechanisms of NP-inspired degraders and discuss the associated
challenges and future opportunities in this field.