2. Academic Validation
  3. Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer

Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer

  • J Med Chem. 2022 Aug 25;65(16):11034-11057. doi: 10.1021/acs.jmedchem.2c00257.
Jiacheng Li 1 2,  Ting Liu 3,  Yuanli Song 2 4,  Mingyu Wang 1 2,  Liping Liu 1 2,  Hongwen Zhu 2 4,  Qi Li 1 2,  Jin Lin 3,  Hualiang Jiang 1 2,  Kaixian Chen 1 2,  Kehao Zhao 5,  Mingliang Wang 1,  Hu Zhou 2 4,  Hua Lin 1 6,  Cheng Luo 3 1 2 7
Affiliations

Affiliations

  • 1 The Center for Chemical Biology, Drug Discovery and Design Center, 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, No.19A Yuquan Road, Beijing 100049, China.
  • 3 School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
  • 4 Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 5 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 6 Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.
  • 7 School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.
PMID: 35925880 DOI: 10.1021/acs.jmedchem.2c00257
Abstract

Aberrant hyperactivation of cyclins results in carcinogenesis and therapy resistance in cancers. Direct degradation of the specific cyclin or cyclin-dependent kinase (CDK)-cyclin complex by small-molecule degraders remains a great challenge. Here, we applied the first application of hydrophobic tagging to induce degradation of CDK9-cyclin T1 heterodimer, which is required to keep productive transcription of oncogenes in cancers. LL-K9-3 was identified as a potent small-molecule degrader of CDK9-cyclin T1. Quantitative and time-resolved proteome profiling exhibited LL-K9-3 induced selective and synchronous degradation of CDK9 and cyclin T1. The expressions of Androgen Receptor (AR) and cMyc were reduced by LL-K9-3 in 22RV1 cells. LL-K9-3 exhibited enhanced anti-proliferative and pro-apoptotic effects compared with its parental CDK9 Inhibitor SNS032 and suppressed downstream signaling of CDK9 and AR more effectively than SNS032. Moreover, LL-K9-3 inhibited AR and Myc-driven oncogenic transcriptional programs and exerted stronger inhibitory effects on several intrinsic target genes of AR than the monomeric CDK9 PROTAC (Thal-SNS032).

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