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  3. Targeted Protein Degradation Induced by HEMTACs Based on HSP90

Targeted Protein Degradation Induced by HEMTACs Based on HSP90

  • J Med Chem. 2023 Jan 12;66(1):733-751. doi: 10.1021/acs.jmedchem.2c01648.
Zhenzhen Li 1,  Siyue Ma 1,  Ling Zhang 1,  Shuxin Zhang 1,  Zhao Ma 1,  Lupei Du 1,  Minyong Li 1 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China.
PMID: 36574496 DOI: 10.1021/acs.jmedchem.2c01648
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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