Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

Mallinger, Aurélie; Schiemann, Kai; Rink, Christian; Stieber, Frank; Calderini, Michel; Crumpler, Simon; Stubbs, Mark; Adeniji-Popoola, Olajumoke; Poeschke, Oliver; Busch, Michael; Czodrowski, Paul; Müsil, Djordje; Schwarz, Dániel; Ortiz-Ruiz, Maria-Jesus; Schneider, Richard; Thai, Ching; Valenti, Melanie; Brandon, Alexis de Haven; Burke, Rosemary; Workman, Paul; Dale, Trevor; Wienke, Dirk; Clarke, Paul A.; Esdar, Christina; Raynaud, Florence I.; Eccles, Suzanne A.; Rohdich, Felix; Blagg, Julian

doi:10.1021/acs.jmedchem.5b01685

Cited by 94 publications

(114 citation statements)

References 39 publications

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“…Burgeoning interest in Mediator-associated kinases as chemotherapeutic targets has prompted development of several structurally distinct CDK8 and CDK19 inhibitors including Δ 16 -cortistatin A (dCA; 5 ), an analog of the potent CDK8- and CDK19-selective natural product cortistatin A 17,18 , and the recently published highly selective CDK8 and CDK19 inhibitor CCT251921 ( 6 ) 19 (Fig. 3a).…”

Section: Resultsmentioning

confidence: 99%

“…The growing interest in Mediator-associated kinases as therapeutic targets in cancer has spurred development of several chemically distinct CDK8 and CDK19 inhibitors such as the potent, dual inhibitor CCT251921 (ref. 19), which shares a pyridinyl tetrahydroquinoline core with BRD6989, and a close analog of the natural product cortistatin A (dCA) 17,27 . Though not as potent as these inhibitors, BRD6989 appears to be unique in its ability to differentially inhibit CDK8 relative to its paralog CDK19, suggesting that it may inform further development of CDK8-specific inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…T-5224 was obtained from ApexBio. HG-9-91-01 and CCT251921 were prepared as described previously 8,19 . Δ 16 -cortistatin A (dCA) was a generous gift from P. Baran (The Scripps Research Institute).…”

Section: Methodsmentioning

confidence: 99%

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Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells

et al. 2017

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Enhancing production of the anti-inflammatory cytokine interleukin-10 (IL-10) is a promising strategy to suppress pathogenic inflammation. To identify new mechanisms regulating IL-10 production, we conducted a phenotypic screen for small molecules that enhance IL-10 secretion from activated dendritic cells. Mechanism-of-action studies using a prioritized hit from the screen, BRD6989, identified the Mediator-associated kinase CDK8, and its paralog CDK19, as negative regulators of IL-10 production during innate immune activation. The ability of BRD6989 to upregulate IL-10 is recapitulated by multiple, structurally differentiated CDK8 and CDK19 inhibitors and requires an intact cyclin C–CDK8 complex. Using a highly parallel pathway reporter assay, we identified a role for enhanced AP-1 activity in IL-10 potentiation following CDK8 and CDK19 inhibition, an effect associated with reduced phosphorylation of a negative regulatory site on c-Jun. These findings identify a function for CDK8 and CDK19 in regulating innate immune activation and suggest that these kinases may warrant consideration as therapeutic targets for inflammatory disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells

et al. 2017

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“…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.…”

Section: Introductionmentioning

confidence: 99%

CDK8 Kinase Activity Promotes Glycolysis

et al. 2017

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SUMMARY Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancerous tissues. Despite its importance in cancer development, our understanding of mechanisms driving this form of metabolic reprogramming is incomplete. We report here an analysis of colorectal cancer cells engineered to carry a single point mutation in the active site of the Mediator-associated kinase CDK8, creating hypomorphic alleles sensitive to bulky ATP analogs. Transcriptome analysis revealed CDK8 kinase activity is required for expression of many components of the glycolytic cascade. CDK8 inhibition impairs glucose transporter expression, glucose uptake, glycolytic capacity and reserve, as well as cell proliferation and anchorage independent growth, both in normoxia and hypoxia. Importantly, CDK8 impairment sensitizes cells to pharmacological glycolysis inhibition, a result reproduced with Senexin A, a dual inhibitor of CDK8/CDK19. Altogether, these results contribute to our understanding of CDK8 as an oncogene and justify investigations to target CDK8 in highly glycolytic tumors.

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“…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). Subsequently, we discovered a second, chemically-distinct series of CDK8/19 ligands and optimization of pharmacological, pharmaceutical and pharmacokinetic properties identified a 3-methyl-1 H -pyrazolo[3,4- b ]pyridine, which also binds to CDK8/CCNC (Czodrowski et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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

Clarke

Ortiz-Ruiz

TePoele

et al. 2016

eLife

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Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.DOI: http://dx.doi.org/10.7554/eLife.20722.001

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Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

Cited by 94 publications

References 39 publications

Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells

Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells

CDK8 Kinase Activity Promotes Glycolysis

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

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