2. Academic Validation
  3. Identification of 3, 4-disubstituted pyridine derivatives as novel CDK8 inhibitors

Identification of 3, 4-disubstituted pyridine derivatives as novel CDK8 inhibitors

  • Eur J Med Chem. 2021 Nov 5:223:113634. doi: 10.1016/j.ejmech.2021.113634.
Haochao Zhang 1,  Liandong Jing 1,  Man Liu 1,  Masuo Goto 2,  Fangfang Lai 3,  Xiao Liu 3,  Li Sheng 3,  Yajun Yang 1,  Ying Yang 1,  Yan Li 3,  Xiaoguang Chen 3,  Kuo-Hsiung Lee 4,  Zhiyan Xiao 5
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, USA.
  • 3 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
  • 5 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: xiaoz@imm.ac.cn.
PMID: 34147745 DOI: 10.1016/j.ejmech.2021.113634
Abstract

Selective inhibition of cyclin-dependent kinase 8 (CDK8) has been recently regarded as a potential approach for Cancer therapy. A series of novel CDK8 inhibitors with the pyridine core was identified via scaffold hopping from the known CDK8 Inhibitor A-7. The new inhibitors were designed to improve the ligand efficiency so as to enhance drug-likeness. Most of the compounds showed significant inhibition against CDK8/cyclin C, and the most active compounds (5d, 5e and 7') displayed IC50 values of 2.4 nM, 5.0 nM and 7.7 nM, respectively. Preliminary kinase profiling of selected compounds against a panel of kinases from different families indicated that this compound class might selectively inhibit CDK8 as well as its paralog CDK19. Some compounds exhibited cellular activity in both MTT and SRB assays against a variety of tumor cells, including HCT-116, A549, MDA-MB-231, KB, KB-VIN and MCF-7. Further flow cytometry analysis revealed a dose-dependent G2/M phase arrest in MDA-MB-231 cells treated with compounds 6'a, 6'b, 6'j and 6'k. In addition, compound 6'k demonstrated moderate antitumor efficacy in HCT-116 mouse models, although unfavorable pharmacokinetic profiles were suggested by preliminary study in mice. The results provided a new structural prototype for the search of selective CDK8 inhibitors as antitumor agents.

Keywords

Antitumor activity; CDK8 inhibitor; Kinase profiling; Ligand efficiency; Pyridine core.

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