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
  • 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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