Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs

J Med Chem. 2023 Sep 28;66(18):12877-12893. doi: 10.1021/acs.jmedchem.3c00828. Epub 2023 Sep 6.

Abstract

Autophagy is an efficient and attractive protein degradation pathway in addition to the ubiquitin-proteasome system. Herein, systematic optimization of coumarin analogs linked with the CDK9 inhibitor SNS-032 is reported that may bind to cyclin-dependent kinase 9 (CDK9) and microtubule-associated protein 1 light chain 3 beta (LC3B) simultaneously, which leads to the selective autophagic degradation of targeted CDK9/cyclin T1 and is different from the PROTAC degrader THAL-SNS-032. Further mechanism studies revealed an autophagy-lysosome pathway, where the degraders possibly formed a ternary complex with CDK9 and LC3B. In addition, degrader 10 showed antitumor efficacy in vivo. Our work optimized a potent LC3B recruiter and demonstrated the feasibility of autophagy-tethering compounds (ATTECs), which could be applied for the degradation of diverse intracellular pathogenic proteins to treat related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Coumarins / pharmacology
  • Cyclin T
  • Cyclin-Dependent Kinase 9*
  • Microtubule-Associated Proteins* / metabolism

Substances

  • N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
  • Cyclin-Dependent Kinase 9
  • Cyclin T
  • Microtubule-Associated Proteins
  • Coumarins