2. Academic Validation
  3. Phenotype-Led Identification of IL-10 Upregulators in Human CD4+ T-cells and Elucidation of Their Pharmacology as Highly Selective CDK8/CDK19 Inhibitors

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. 2025 Jan 23;68(2):1883-1900. doi: 10.1021/acs.jmedchem.4c02630.
Simon Nicolle 1,  Mike Barker 1,  John Barrett 2,  Matthew Campbell 1,  Justyna Wojno-Picon 1,  Stephen J Atkinson 1,  Helen Aylott 1,  Hripsimee Kessedjian 1,  Yanan He 3,  Cassie Messenger 1,  Emma Roberts 1,  Claus Spitzfaden 1,  Joelle Le 1,  Nico Zinn 4,  Thilo Werner 4,  Birgit Dümpelfeld 4,  Marcus Bantscheff 4,  Don O Somers 1,  Heather Reid 5,  Kevin Thang 5,  Thomas Gobbetti 5,  Huw D Lewis 5
Affiliations

Affiliations

  • 1 Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 2 In Vitro In Vivo Translation, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 3 Medicine Development and Supply, GlaxoSmithKline R&D Hub, 1250 South Collegeville Road, Upper Providence, Pennsylvania 19426, United States.
  • 4 Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg 69117, Germany.
  • 5 Immunology Research Unit GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
PMID: 39780505 DOI: 10.1021/acs.jmedchem.4c02630
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. In vitro optimization of the initial hit yielded a lead with good potency and an in vitro 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.

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