化学
体外
细胞周期蛋白依赖激酶
激酶
铅化合物
高通量筛选
生物化学
细胞
细胞周期
作者
Simon Nicolle,Mike D. Barker,J. Carl Barrett,Matthew Campbell,Justyna Wojno-Picon,Stephen J. Atkinson,Helen Aylott,Hripsimée Kessedjian,Yanan He,Cassie Messenger,Emma J. Roberts,Claus Spitzfaden,Joelle Le,Nico Zinn,Thilo Werner,Birgit Dümpelfeld,Marcus Bantscheff,Don O. Somers,Heather L. Reid,Kevin Thang,Thomas Gobbetti,Huw D. Lewis
标识
DOI:10.1021/acs.jmedchem.4c02630
摘要
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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