Discovery of HyT-Based Degraders of CDK9-Cyclin T1 Complex

  • Chem Biodivers. 2023 Aug;20(8):e202300769. doi: 10.1002/cbdv.202300769.
Rongkun Lin  1 ,  Jie Yang  2 ,  Ting Liu  1 ,  Mingyu Wang  3  4 ,  Chongrong Ke  5 ,  Cheng Luo  1  3  4  6  7 ,  Jin Lin  1 ,  Jiacheng Li  3  4 ,  Hua Lin  2
Affiliations
  • 1. School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China.
  • 2. Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou, 350117, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5. National and Local United Engineering Research Center of Industrial Microbiology and Fermentation Technology, College of Life Sciences, Fujian Normal University, Fuzhou, 350117, Fujian, China.
  • 6. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China.
  • 7. Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
PMID: 37349855 DOI: 10.1002/cbdv.202300769
Abstract

Direct modulation of the non-kinase functions of cyclin and CDK-cyclin complexes poses challenges. We utilize hydrophobic tag (HyT) based small-molecule degraders induced degradation of cyclin T1 and its corresponding kinase partner CDK9. LL-CDK9-12 demonstrated the most potent and selective degradation ability, with DC50 values of 0.362 μM against CDK9 and 0.680 μM against cyclin T1. In prostate Cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032 and LL-K9-3, the previous reported CDK9-cyclin T1 degrader. Moreover, LL-CDK9-12 suppressed the downstream signaling of CDK9 and AR efficiently. Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and helped study the unknown function of CDK9-cyclin T1. These results suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes' degraders.

Keywords
CDK9; cyclin T1; degrader; hydrophobic tag; protein degradation.
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