Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs.
Yanping ZengJian XiaoYuanxin XuFan WeiLina TianYinglei GaoYi ChenYouhong HuPublished in: Journal of medicinal chemistry (2023)
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.
Keyphrases
- cell cycle
- cell death
- cell proliferation
- cell cycle arrest
- endoplasmic reticulum stress
- signaling pathway
- fluorescent probe
- simultaneous determination
- oxidative stress
- mass spectrometry
- molecular docking
- liquid chromatography
- protein kinase
- single cell
- living cells
- reactive oxygen species
- pi k akt
- tandem mass spectrometry
- amino acid
- molecular dynamics simulations
- single molecule