title: Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
abstract: The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Mallinger
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Schiemann
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Christian
authors.initials: C
authors.lastname: Rink
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Stieber
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Calderini
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Simon
authors.initials: S
authors.lastname: Crumpler
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Mark
authors.initials: M
authors.lastname: Stubbs
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Olajumoke
authors.initials: O
authors.lastname: Adeniji-Popoola
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Poeschke
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Busch
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Czodrowski
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Djordje
authors.initials: D
authors.lastname: Musil
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schwarz
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Ortiz-Ruiz
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Ching
authors.initials: C
authors.lastname: Thai
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Alexis
authors.initials: A
authors.lastname: de Haven Brandon
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burke
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.affiliation: School of Bioscience, Cardiff University , Cardiff, CF10 3AX, U.K.
authors.forename: Trevor
authors.initials: T
authors.lastname: Dale
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wienke
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Esdar
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.affiliation: Merck KGaA , Darmstadt, 64293, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Rohdich
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D054852:Small Molecule Libraries; C584437:CDK19 protein, human; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases; C032439:alpha-aminopyridine