Molecular glues(MGs), a class of small-molecule degraders, exhibit drug-like properties that generally conform to Lipinski's rule of five, while uniquely mediating the stabilization or induction of protein-protein...Molecular glues(MGs), a class of small-molecule degraders, exhibit drug-like properties that generally conform to Lipinski's rule of five, while uniquely mediating the stabilization or induction of protein-protein interactions. By altering the surface properties of either target proteins or E3 ligases, MGs promote the formation of a ternary complex comprising the MG, an E3 ligase, and a target protein. This interaction facilitates the polyubiquitination and subsequent degradation of the target protein via the ubiquitin-proteasome system.Owing to its distinctive mechanism of action and broad therapeutic potential, MG is offering novel approaches to disease treatment. This review summarizes recent advances in MGs targeting NEK7, WEE1, CDK2, GSPT1 and VAV1, emphasizing the rational design, benefits,and potential limitations, highlighting rational design principles, advantages, and current limitations including challenges in achieving selectivity and rational design that provide critical insights for enhancing MG efficacy. These developments are crucial for advancing the application and optimization of molecular glues targeting NEK7, WEE1, CDK2, GSPT1and VAV1.展开更多
基金supported by the National Natural Science Foundation of China (No. 82304306)the Hubei Key Laboratory of Kidney Disease Occurrence and Intervention Development Fund (No. 2023SB108)+4 种基金the Huangshi City Science and Innovation Team Project of China (CXPT2023000002)the talent introduction program from Hubei Polytechnic University (No.19XJK07R)the Department of Education of Hubei Provincial Science and Technology Research Project (No. D20234502)the PostDoctoral Research Start-up Fund of Lishui People's Hospital, Zhejiang, China (2023bsh002)the Zhejiang Provincial Postdoctoral Research Project of Meritorious Support (ZJ2024007)。
文摘Molecular glues(MGs), a class of small-molecule degraders, exhibit drug-like properties that generally conform to Lipinski's rule of five, while uniquely mediating the stabilization or induction of protein-protein interactions. By altering the surface properties of either target proteins or E3 ligases, MGs promote the formation of a ternary complex comprising the MG, an E3 ligase, and a target protein. This interaction facilitates the polyubiquitination and subsequent degradation of the target protein via the ubiquitin-proteasome system.Owing to its distinctive mechanism of action and broad therapeutic potential, MG is offering novel approaches to disease treatment. This review summarizes recent advances in MGs targeting NEK7, WEE1, CDK2, GSPT1 and VAV1, emphasizing the rational design, benefits,and potential limitations, highlighting rational design principles, advantages, and current limitations including challenges in achieving selectivity and rational design that provide critical insights for enhancing MG efficacy. These developments are crucial for advancing the application and optimization of molecular glues targeting NEK7, WEE1, CDK2, GSPT1and VAV1.
