title: 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.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paul A
authors.identifier: 0000-0001-9342-1290
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Ortiz-Ruiz
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: TePoele
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Olajumoke
authors.initials: O
authors.lastname: Adeniji-Popoola
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Will
authors.initials: W
authors.lastname: Court
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Czasch
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Samer
authors.initials: S
authors.lastname: El Bawab
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Esdar
authors.affiliation: School of Bioscience, Cardiff University, Cardiff, United Kingdom.
authors.forename: Ken
authors.initials: K
authors.lastname: Ewan
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Sharon
authors.initials: S
authors.lastname: Gowan
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Alexis
authors.initials: A
authors.lastname: De Haven Brandon
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Phillip
authors.initials: P
authors.lastname: Hewitt
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hobbs
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kaufmann
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Mallinger
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Toby
authors.initials: T
authors.lastname: Roe
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Rohdich
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Schiemann
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Simon
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Weigt
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Julian
authors.identifier: 0000-0002-7409-0323
authors.initials: J
authors.lastname: Blagg
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Andree
authors.initials: A
authors.lastname: Blaukat
authors.affiliation: School of Bioscience, Cardiff University, Cardiff, United Kingdom.
authors.forename: Trevor C
authors.initials: TC
authors.lastname: Dale
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hecht
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Urbahns
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paul
authors.identifier: 0000-0003-1659-3034
authors.initials: P
authors.lastname: Workman
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wienke
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000633:toxicity; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy; D056892:Mediator Complex / Q000037:antagonists & inhibitors*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000633:toxicity; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D056892:Mediator Complex; D047428:Protein Kinase Inhibitors; C584437:CDK19 protein, human; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases
keywords: CDK8; Mediator complex; Wnt; cancer biology; human; human biology; inhibitor; medicine; super-enhancer