2. Academic Validation
  3. Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex

Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex

  • J Med Chem. 2023 Apr 13;66(7):4932-4951. doi: 10.1021/acs.jmedchem.2c02045.
Mingyu Wang 1 2,  Rongkun Lin 3,  Jiacheng Li 1 2,  Yuying Suo 1 2,  Jing Gao 4,  Liping Liu 1 2,  Liyuan Zhou 5,  Yicheng Ni 5,  Ziqun Yang 2 6,  Jie Zheng 2 6,  Jin Lin 3,  Hu Zhou 1 2,  Cheng Luo 3 1 2 7 5,  Hua Lin 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
  • 4 Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 6 Center of Immunological Diseases, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China.
PMID: 36930701 DOI: 10.1021/acs.jmedchem.2c02045
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.

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