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• W3055246865 abstract "Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation." @default.
• W3055246865 created "2020-08-24" @default.
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• W3055246865 date "2020-08-17" @default.
• W3055246865 modified "2023-10-16" @default.
• W3055246865 title "Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation" @default.
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• W3055246865 doi "https://doi.org/10.7554/elife.59994" @default.
• W3055246865 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7462607" @default.
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