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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.

 

Comments:

It sounds like you're discussing a fascinating study involving the optimization of compounds linked to the CDK9 inhibitor SNS-032, aiming to bind to CDK9 and microtubule-associated protein 1 light chain 3 beta (LC3B) concurrently. This binding potentially triggers selective autophagic degradation of targeted proteins, specifically CDK9/cyclin T1. This approach differs from THAL-SNS-032, a PROTAC degrader.

The mechanism studies highlighted the involvement of the autophagy-lysosome pathway, suggesting that the degraders may form a ternary complex with CDK9 and LC3B. Furthermore, one of the optimized compounds demonstrated antitumor efficacy in vivo, indicating its potential for therapeutic application.

This work seems significant as it not only optimized a potent LC3B recruiter but also showcased the feasibility of using autophagy-tethering compounds (ATTECs) for degrading various intracellular pathogenic proteins. This could potentially offer new avenues for treating diseases associated with such proteins.

It's exciting to see advancements in leveraging autophagy as a mechanism for targeted protein degradation, opening doors for innovative therapeutic strategies.

Related Products

Cat.No. Product Name Information
S8979 THAL-SNS-032 THAL-SNS-032 is a selective Cyclin-dependent kinase 9 (CDK9) degrader PROTAC consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN).

Related Targets

CDK PROTAC E3 Ligase