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

Abstract

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

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

“…Several groups are currently in the process of developing CDK8/19 inhibitors for cancer therapy applications (18). Although a recent paper reported significant toxicity of two CDK8/19-inhibiting small molecules (19), no toxicity has been reported in animal studies with other CDK8/19 inhibitors, including those used in the present work (3,8,16,17).…”

CDK8 Kinase Activity Promotes Glycolysis

“…The discovery of CDK8 as a CRC oncogene has generated considerable interest in its therapeutic targeting in various cancer types, and numerous small molecule inhibitors have been reported recently, all of which inhibit both CDK8 and its highly similar paralog CDK19 (Clarke et al, 2016). Many of these compounds have demonstrated efficacy in vitro and in preclinical models, most notably Cortistatin A in AML cells (Pelish et al, 2015), Senexin A in fibrosarcoma cells (Porter et al, 2012), and CCT251921 and MSC2530818 in CRC cells (Clarke et al, 2016).…”

“…Many of these compounds have demonstrated efficacy in vitro and in preclinical models, most notably Cortistatin A in AML cells (Pelish et al, 2015), Senexin A in fibrosarcoma cells (Porter et al, 2012), and CCT251921 and MSC2530818 in CRC cells (Clarke et al, 2016). However, the most comprehensive evaluation of the therapeutic potential of dual CDK8/19 inhibitors to date, using two different classes of compounds, demonstrated only modest activity in a β-catenin-driven mouse model of CRC, and various adverse effects in rat and dog tolerability studies (Clarke et al, 2016). Although the mouse model was not driven by CDK8 amplification, these results nonetheless suggest that on-target activity will lead to adverse effects that would limit the therapeutic application of these dual CDK8/19 inhibitors as single agents.…”

“…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.…”

“…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. Furthermore, while studies using mouse models demonstrated reduced tumor growth, testing in rats and dogs suggested that therapeutic application of dual CDK8/19 inhibitors could be limited due to adverse effects in a range of tissues (Clarke et al, 2016). Therefore, elucidating the functional specialization of CDK8 versus CDK19 and their relative value as therapeutic targets in cancer is a high priority.…”