9H8C

Human CDK8/Cyclin-C complex with inhibitor 2-9

This is a non-PDB format compatible entry.

Summary for 9H8C

• Entry DOI: 10.2210/pdb9h8c/pdb
• Descriptor: Cyclin-dependent kinase 8, Cyclin-C, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: kinase, inhibitor, cdk8, cyclin dependent kinase, cyclin, transcription-transferase-inhibitor complex, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 85290.91

Authors

Somers, D.O. (deposition date: 2024-10-29, release date: 2025-01-22, Last modification date: 2025-02-05)

Primary citation

Nicolle, S.,Barker, M.,Barrett, J.,Campbell, M.,Wojno-Picon, J.,Atkinson, S.J.,Aylott, H.,Kessedjian, H.,He, Y.,Messenger, C.,Roberts, E.,Spitzfaden, C.,Le, J.,Zinn, N.,Werner, T.,Dumpelfeld, B.,Bantscheff, M.,Somers, D.O.,Reid, H.,Thang, K.,Gobbetti, T.,Lewis, H.D.
Phenotype-Led Identification of IL-10 Upregulators in Human CD4 + T-cells and Elucidation of Their Pharmacology as Highly Selective CDK8/CDK19 Inhibitors.
J.Med.Chem., 68:1883-1900, 2025

PubMed Abstract: Therapeutics promoting the endogenous production of IL-10 have the potential to restore homeostasis in inflammatory disorders such as inflammatory bowel disease (IBD). Here we describe the identification of a series of IL-10 upregulators based on a pyrimidyl-piperidine scaffold through a high throughput phenotypic CD4 T-cell multiplex assay. optimization of the initial hit yielded a lead with good potency and an clearance profile, compound 3-7, which additionally demonstrated efficacy in a murine endotoxin challenge PK-PD mechanistic model. Target deconvolution efforts identified compound 3-7 as a highly selective CDK8/19 inhibitor, and crystallographic studies unveiled its binding mode to the CDK8/Cyclin-C complex, characterized by an unusual water-mediated hydrogen bond to the kinase hinge region.

PubMed: 39780505
DOI: 10.1021/acs.jmedchem.4c02630

Experimental method

X-RAY DIFFRACTION (2.573 Å)