Proteolysis targeting chimeric drugs and their potential risks

doi:10.19803/j.1672-8629.20240423

Abstract

Abstract: Objective To introduce the mechanism and design principles of protein hydrolysis targeting chimeras (PROTACs) in Targeted Protein Degradation (TPD) technology, and to discuss the potential risks of and solutions to existing PROTACs based drugs in order to provide reference for the development of new, efficient and safe PROTAC drugs. Methods Relevant literature published in recent years was analyzed. The mechanism of PROTACs technology, design principles of each component, identified potential risks, and corresponding response strategies were summarized. Results For the design of PROTAC drugs, suitable sites and connecting chains should be selected from the solvent exposure areas of target protein binding molecules. At the same time, this design should be based on high-resolution crystal structures and avoid changes in the binding affinity between small molecules and target proteins. For the selection of E3 ligases and their ligands, screening usually starts with the widely used CRBN and VHL ligands. In the design of connecting chains, screening often starts from flexible PEG chains. In terms of potential risks, PROTAC drugs can cause such problems as excessive degradation, off target toxicity, Hook effect, metabolite toxicity, involvement of aldehyde oxidase in metabolism, and linker cleavage product toxicity. Conclusion PTOTAC compounds should be viewed as a whole, and proteomics and other technical methods should be flexibly applied to prevent, monitor and analyze the toxicity of their metabolites so as to facilitate the development of more active and safe PROTAC drugs.

Key words: targeted protein degradation, proteolysis targeting chimeras, potential risks, proteomics, security

CLC Number:

R977
R979.1

JIANG Hailun, ZHOU Xinbo, XIAO Dian, ZHONG Wu, LI Song. Proteolysis targeting chimeric drugs and their potential risks[J]. Chinese Journal of Pharmacovigilance, 2024, 21(7): 730-734.

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https://zgywjj.magtechjournal.com/EN/Y2024/V21/I7/730

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