9h8c
Human CDK8/Cyclin-C complex with inhibitor 2-9
Structural highlights
FunctionCDK8_HUMAN Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.[1] [2] Publication Abstract from PubMedTherapeutics 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. Phenotype-Led Identification of IL-10 Upregulators in Human CD4(+) T-cells and Elucidation of Their Pharmacology as Highly Selective CDK8/CDK19 Inhibitors.,Nicolle S, Barker M, Barrett J, Campbell M, Wojno-Picon J, Atkinson SJ, Aylott H, Kessedjian H, He Y, Messenger C, Roberts E, Spitzfaden C, Le J, Zinn N, Werner T, Dumpelfeld B, Bantscheff M, Somers DO, Reid H, Thang K, Gobbetti T, Lewis HD J Med Chem. 2025 Jan 8. doi: 10.1021/acs.jmedchem.4c02630. PMID:39780505[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
