Phenotype-Led Identification of IL-10 Upregulators in Human CD4<sup>+</sup> T-cells and Elucidation of Their Pharmacology as Highly Selective CDK8/CDK19 Inhibitors

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<sup>+</sup> T-cell multiplex assay. <i>In vitro</i> optimization of the initial hit yielded a lead with good potency and an <i>in vitro</i> 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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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-01-09
DOI
https://doi.org/10.1021/acs.jmedchem.4c02630
Citations
1
Primary Topic
Tuberculosis Research and Epidemiology
Type
article
Field-Weighted Citation Impact
1.40
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article

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

Birgit Dümpelfeld, Thomas Gobbetti, Hripsimée Kessedjian, Don O. Somers et al.
1 citations
Journal of Medicinal Chemistry
Tuberculosis Research and Epidemiology
1.40
article

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

Birgit Dümpelfeld, Thomas Gobbetti, Hripsimée Kessedjian, Don O. Somers, Claus Spitzfaden, Huw D. Lewis, Joelle Le, Thilo Werner, Helen Aylott, Cassie Messenger, Emma J. Roberts, Nico Zinn, Marcus Bantscheff, Stephen J. Atkinson, Justyna Wojno-Picon, Mike D. Barker, Yanan He, Matthew Campbell, Heather L. Reid, J. Carl Barrett, Simon Nicolle, Kevin Thang
article en
1 citations

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<sup>+</sup> T-cell multiplex assay. <i>In vitro</i> optimization of the initial hit yielded a lead with good potency and an <i>in vitro</i> 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.

Journal of Medicinal ChemistryVol. 68(2)
University of Hertfordshire (GB), GlaxoSmithKline (United Kingdom) (GB), Providence College (US), South College (US), North Hertfordshire College (GB), GlaxoSmithKline (United States) (US), GlaxoSmithKline (Germany) (DE), Warren Spring Laboratory (GB)
Zero hunger
Openalex Percentile: Top 25%
Tuberculosis Research and Epidemiology
1.40
DOISourceOpenAlex
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