A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease

Abstract

There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small molecule WNT-pathway inhibitor discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a Type 1 binding mode involving insertion of the CDK8 C-terminus into the ligand binding site. InReprints and permissions information is available online at http://www.nature.com/reprints/index.html.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

Comprehensive Effects of Suppression of MicroRNA-383 in Human Bone-Marrow-Derived Mesenchymal Stem Cells on Treating Spinal Cord Injury

“…CDK8 and CDK19 are found to be associate with identical mediator complexes, but appear to have non-redundant function and sometime even play opposite roles in VP16-dependent transcription, largely due to their difference in C-terminal regions [15]. As a critical factor involved in cell-cycle turnover, augmentation of CDK19 was expected to increase MSC proliferation, which was confirmed in the current study.…”

“…CDK19 is previously known as CDK8-like, CDK8L or CDC2L6, due to its high amino acid sequence conservation with CDK8 [15]. CDK8 and CDK19 are found to be associate with identical mediator complexes, but appear to have non-redundant function and sometime even play opposite roles in VP16-dependent transcription, largely due to their difference in C-terminal regions [15].…”

CDK8 Kinase Activity Promotes Glycolysis

“…Despite the obvious importance of Mediator in gene expression control, little is known about shared and unique functions of the CDK-module paralogs. Recently, a number of dual inhibitors of CDK8 and CDK19 have been developed, including Cortistatin A, Senexin A, CCT251921 and MSC2530818 (Cee et al, 2009; Clarke et al, 2016; Czodrowski et al, 2016; Dale et al, 2015; Koehler et al, 2016; Mallinger et al, 2015; Mallinger et al, 2016a; Mallinger et al, 2016b; Porter et al, 2012; Schiemann et al, 2016). While many of these compounds appear to have efficacy against cancer cell lines in vitro , it remains unclear whether the effects are due to inhibition of CDK8, CDK19 or both.…”

Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases

“…Previously, we reported the discovery and optimization of a potent and selective 3,4,5-trisubstituted pyridine series of small-molecule inhibitors of WNT signaling from a cell-based pathway screen, and using a chemo-proteomic strategy we identified CDK8 and CDK19 as the primary molecular targets (Dale et al, 2015; Boyer, 2015). Through further optimization we identified a potent, highly selective and orally bioavailable dual CDK8/19 ligand with excellent cell-based activity and pharmaceutical properties (Mallinger et al, 2016a).…”