2. Academic Validation
  3. Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

  • J Med Chem. 2022 Oct 27;65(20):13533-13560. doi: 10.1021/acs.jmedchem.2c01223.
Jiao Li 1 2,  Zhenyu Cai 3,  Xu-Wen Li 4 5,  Chunlin Zhuang 1 2
Affiliations

Affiliations

  • 1 Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 3 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 36205223 DOI: 10.1021/acs.jmedchem.2c01223
Abstract

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.

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