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

Basic Information

ID: ALA4330136

Journal: Bioorg Med Chem Lett

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

Authors: He LJ, Zhu YB, Fan QZ, Miao DD, Zhang SP, Liu XP, Zhang C.

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) (STAT1^SER727), 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.

CiteXplore: 30630717

DOI: 10.1016/j.bmcl.2018.12.065

Patent ID: ┄

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