Shape-based virtual screen for the discovery of novel CDK8 inhibitor chemotypes

  • Bioorg Med Chem Lett. 2019 Feb 15;29(4):549-555. doi: 10.1016/j.bmcl.2018.12.065.
Lian-Jun He  1 ,  Yi-Bao Zhu  1 ,  Qing-Zhu Fan  1 ,  Dong-Dong Miao  1 ,  Sheng-Peng Zhang  2 ,  Xiao-Ping Liu  3 ,  Chao Zhang  4
Affiliations
  • 1. Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui 241000, PR China.
  • 2. Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui 241000, PR China; School of Pharmacy, Wannan Medical College, Wuhu, Anhui 241000, PR China.
  • 3. Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui 241000, PR China. Electronic address: [email protected].
  • 4. Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui 241000, PR China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wannan Medical College, Wuhu, Anhui 241000, PR China; School of Pharmacy, Wannan Medical College, Wuhu, Anhui 241000, PR China. Electronic address: [email protected].
PMID: 30630717 DOI: 10.1016/j.bmcl.2018.12.065
Abstract

With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal Cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1SER727), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential Cancer therapeutic agent.

Keywords
Antitumor; CDK8; ROCKs; Virtual screen.
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