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

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.