title: Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.
abstract: The mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.
authors.affiliation: Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Czodrowski
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 , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wienke
authors.affiliation: Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Esdar
authors.affiliation: Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Pöschke
authors.affiliation: Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Busch
authors.affiliation: Merck KGaA , Frankfurter Strasse 250, 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: Suzanne A
authors.initials: SA
authors.lastname: Eccles
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 , Frankfurter Strasse 250, 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: 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: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Djordje
authors.initials: D
authors.lastname: Musil
authors.affiliation: Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schwarz
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 , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Urbahns
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
authors.affiliation: Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Schiemann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8