Cyclin-dependent kinase 9(CDK9)is a member of the transcription CDK subfamily and plays a role in transcriptional regulation.Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors....Cyclin-dependent kinase 9(CDK9)is a member of the transcription CDK subfamily and plays a role in transcriptional regulation.Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors.Herein,we report the first ATG101-recruiting selective CDK9 degrader,AZ-9,based on the hydrophobic tag kinesin degradation technology.AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo,which could also affect downstream related phenotypes.Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy–lysosome pathway,and forms autophagosomes through the recruitment of LC3,which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1.These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time,which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.展开更多
Targeted protein degrader has emerged as a transformative therapeutic technology,offering a novel modality to address previously intractable drug targets and enabling innovative approaches to disease treatment1.Unlike...Targeted protein degrader has emerged as a transformative therapeutic technology,offering a novel modality to address previously intractable drug targets and enabling innovative approaches to disease treatment1.Unlike conventional small-molecule drugs that function through occupancy-driven mechanisms,targeted protein degradation(TPD)employs an event-driven pharmacological strategy by harnessing the ubiquitin–proteasome system(UPS)and lysosomal degradation pathways2.展开更多
基金supported by Key R&D Program of Shandong Province,China(No.2024CXPT028)National Natural Science Foundation of China(22177079,22477085)+2 种基金National Natural Science Foundation of Shanghai Province,China(No.24ZR1477400)National Natural Science Foundation of Shandong Province,China(No.ZR2024QC286)Taishan Scholar Foundation of Shandong Province(tstp0648,China).
文摘Cyclin-dependent kinase 9(CDK9)is a member of the transcription CDK subfamily and plays a role in transcriptional regulation.Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors.Herein,we report the first ATG101-recruiting selective CDK9 degrader,AZ-9,based on the hydrophobic tag kinesin degradation technology.AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo,which could also affect downstream related phenotypes.Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy–lysosome pathway,and forms autophagosomes through the recruitment of LC3,which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1.These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time,which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.
文摘Targeted protein degrader has emerged as a transformative therapeutic technology,offering a novel modality to address previously intractable drug targets and enabling innovative approaches to disease treatment1.Unlike conventional small-molecule drugs that function through occupancy-driven mechanisms,targeted protein degradation(TPD)employs an event-driven pharmacological strategy by harnessing the ubiquitin–proteasome system(UPS)and lysosomal degradation pathways2.
