2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19

Mallinger, Aurélie; Schiemann, Kai; Rink, Christian; Sejberg, Jimmy J. P.; Honey, Mark A.; Czodrowski, Paul; Stubbs, Mark; Poeschke, Oliver; Busch, Michael; Schneider, Richard; Schwarz, Dániel; Müsil, Djordje; Burke, Rosemary; Urbahns, Klaus; Workman, Paul; Wienke, Dirk; Clarke, Paul A.; Raynaud, Florence I.; Eccles, Suzanne A.; Esdar, Christina; Rohdich, Felix; Blagg, Julian

doi:10.1021/acsmedchemlett.6b00022

Cited by 41 publications

(47 citation statements)

References 13 publications

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“…During the optimisation of both the 3,4,5-trisubstituted pyridine and 3-methyl-1 H -pyrazolo[3,4- b ]pyridine series, we were unable to separate CDK8 from CDK19 affinity (Mallinger et al, 2015, 2016a; Czodrowski et al, 2016). This is also true for two additional distinct chemical series that we identified (Schiemann et al, 2016; Mallinger et al, 2016b), and also for a further three chemotypes we profiled from the literature, all of which demonstrated balanced CDK8 and CDK19 affinity in our hands. Similarly, the natural product cortistatin A cannot selectively distinguish between CDK8 and 19 (Pelish et al, 2015).…”

Section: Discussionsupporting

confidence: 68%

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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Section: Discussionsupporting

confidence: 68%

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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“…Moreover, considering their enzymatic activity, CDK19 and CDK8 might be more amenable to inhibition by small molecule compounds that Mediator subunits which exclusively act as transcription factors. Based on these observations, both CDK8 and CDK19 have emerged as promising therapeutic targets leading to the development of small molecule inhibitors impeding CDK8 and CDK19 activity …”

Section: Introductionmentioning

confidence: 99%

“…Based on these observations, both CDK8 and CDK19 have emerged as promising therapeutic targets leading to the development of small molecule inhibitors impeding CDK8 and CDK19 activity. 22,[29][30][31][32][33][34][35] In a recent systematic analysis of Mediator complex expression across all major cancer entities using The Cancer Genome Atlas (TCGA), we identified high CDK19 RNA expression specifically in prostate cancer (PCa). 36 Subsequent in vitro experiments highlighted the potential functional implication of CDK19 in PCa progression mainly by promoting the metastatic potential of PCa cells.…”

Section: Introductionmentioning

confidence: 99%

Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer

Becker

Joerg

Hupe

et al. 2019

Intl Journal of Cancer

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The Mediator complex is a transcriptional regulator interacting with transcription factors and RNA‐polymerase‐II. Recently, we identified its subunit CDK19 to be specifically expressed in prostate cancer (PCa) and to be functionally implicated in PCa aggressiveness. Aim of our study was to comprehensively characterize the protein expression of CDK19 and its paralog CDK8 in PCa. We performed immunohistochemistry (IHC) for CDK19/CDK8 on a large cohort including needle biopsies from 202 patients, 799 primary tumor foci of radical prostatectomy specimens from 415 patients, 120 locally advanced tumor foci obtained by palliative transurethral resection, 140 lymph node metastases, 67 distant metastases and 82 benigns. Primary tumors were stained for the proliferation marker Ki67, androgen receptor (AR) and ERG. For 376 patients, clinic–pathologic data were available. Primary endpoint was disease‐recurrence‐free survival (DFS). Nuclear CDK19 and CDK8 expression increases during progression showing the highest intensity in metastatic and castration‐resistant tumors. High CDK19 expression on primary tumors correlates with DFS independently from Gleason grade and PSA. Five‐year‐DFS rates of patients with primary tumors expressing no, moderate and high CDK19 are 73.7, 56.9 and 30.4%, respectively. CDK19 correlates with Gleason grade, T‐stage, Ki67 proliferation‐index, nuclear AR expression and ERG‐status. Therapeutic options for metastatic and castration‐resistant PCa remain limited. In the current study, we confirmed an important role of the Mediator subunit CDK19 in advanced PCa supporting current developments to target CDK19 and its paralog CDK8. Furthermore, CDK19 protein expression has the potential to predict disease recurrence independently from established biomarkers thus contributing to individual management for PCa patients.

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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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2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19

Cited by 41 publications

References 13 publications

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

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

Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer

CDK8 Kinase Activity Promotes Glycolysis

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