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Published on: November 9, 2020
Targeted Protein Degradation Induced by HEMTACs Based on HSP90
Zhenzhen Li1, Siyue Ma1, Ling Zhang1
1Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Abstract:
Targeted protein degradation (TPD) strategies open up new avenues for therapeutics and provide powerful tools for biological inquiry. Herein, we present a brand-new approach, termed heat shock protein 90 (HSP90)-mediated targeting chimeras (HEMTACs), to induce intracellular protein degradation by bridging a target protein to HSP90 to drive the downregulation of proteins. We successfully showcase HEMTACs for cyclin-dependent kinase 4 and 6 (CDK4/6) by using a flexible linker to connect the targeting warhead of CDK4/6 with the HSP90 ligand. Overall, our study delivers a series of evidence that HEMTACs can serve as a valuable addition to TPD strategies, most prominently proteolysis-targeting chimera technology.
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