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- W4327711437 abstract "The CDK8–cyclin C complex is an important anti-tumor target, but unlike CDK8, cyclin C remains undruggable. Modulators regulating cyclin C activity directly are still under development. Here, a series of hydrophobic tagging-based degraders of the CDK8–cyclin C complex were designed, synthesized, and evaluated to identify the first dual degrader, LL-K8-22, which induced selective and synchronous degradation of CDK8 and cyclin C. Proteomic and immunoblot studies exhibited that LL-K8-22 significantly degraded CDK8 without reducing CDK19 and did not degrade other cyclin proteins except cyclin C. Moreover, LL-K8-22 showed enhanced anti-proliferative effects over its parental molecule, BI-1347, with potency increased by 5-fold in MDA-MB-468 cells. LL-K8-22 exhibited more pronounced effects on CDK8–cyclin C downstream signaling than BI-1347, suppressing STAT1 phosphorylation more persistently. RNA-sequencing analysis revealed that LL-K8-22 inhibited E2F- and MYC-driven carcinogenic transcriptional programs. Overall, LL-K8-22 is the first-in-class degrader of cyclin C and would be useful for studying the unknown functions of cyclin C." @default.
- W4327711437 created "2023-03-18" @default.
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- W4327711437 date "2023-03-17" @default.
- W4327711437 modified "2023-10-15" @default.
- W4327711437 title "Discovery of <b>LL-K8-22</b>: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex" @default.
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- W4327711437 doi "https://doi.org/10.1021/acs.jmedchem.2c02045" @default.
- W4327711437 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36930701" @default.
- W4327711437 hasPublicationYear "2023" @default.
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