Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation

J Med Chem. 2022 Jul 14;65(13):8798-8827. doi: 10.1021/acs.jmedchem.2c00728. Epub 2022 Jun 28.

Abstract

Proteolysis-targeting chimeras (PROTACs) is a fast-growing technology providing many strengths over inhibition of protein activity directly and is attracting increasing interest in new drug discovery and development. However, efficiently identifying potent and drug-like degraders is still challenging in the development of PROTACs. Complementary to traditional PROTACs, several emerging types of PROTACs, such as homobivalent PROTACs based on two E3 ligases (e.g., CRBN, VHL, MDM2, TRIM24), chemical- or biological-based trivalent/multitargeted PROTACs, and covalent PROTACs, are rising for targeted protein degradation. These new types of PROTACs have several advantages over the traditional PROTACs including high selectivity, low toxicity, better therapeutic effects, and so on. In this perspective, we will summarize the latest development of representative PROTACs focusing on research mainly in past 10 years and discuss their advantages and disadvantages. Moreover, the outlook and perspectives on the associated challenges and future directions will be provided.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chimera* / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Proteolysis
  • Ubiquitin-Protein Ligases* / metabolism
  • Ubiquitination

Substances

  • Intercellular Signaling Peptides and Proteins
  • snake venom protein C activator
  • Ubiquitin-Protein Ligases