title: Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore.
abstract: Here we describe the discovery and optimization of 3-benzylindazoles as potent and selective inhibitors of CDK8, also modulating CDK19, discovered from a high-throughput screening (HTS) campaign sampling the Merck compound collection. The primary hits with strong HSP90 affinity were subsequently optimized to potent and selective CDK8 inhibitors which demonstrate inhibition of WNT pathway activity in cell-based assays. X-ray crystallographic data demonstrated that 3-benzylindazoles occupy the ATP binding site of CDK8 and adopt a Type I binding mode. Medicinal chemistry optimization successfully led to improved potency, physicochemical properties and oral pharmacokinetics. Modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8, was demonstrated in an APC-mutant SW620 human colorectal carcinoma xenograft model following oral administration.
authors: Merck KGaA, 64293 Darmstadt, Germany. Electronic address: kai.schiemann@merckgroup.com.
authors: Kai
authors: K
authors: Schiemann
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SW7 3RP, UK.
authors: Aurélie
authors: A
authors: Mallinger
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Dirk
authors: D
authors: Wienke
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Christina
authors: C
authors: Esdar
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Oliver
authors: O
authors: Poeschke
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Michael
authors: M
authors: Busch
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Felix
authors: F
authors: Rohdich
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SW7 3RP, UK.
authors: Suzanne A
authors: SA
authors: Eccles
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Richard
authors: R
authors: Schneider
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SW7 3RP, UK.
authors: Florence I
authors: FI
authors: Raynaud
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Paul
authors: P
authors: Czodrowski
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Djordje
authors: D
authors: Musil
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Daniel
authors: D
authors: Schwarz
authors: Merck KGaA, 64293 Darmstadt, Germany.
authors: Klaus
authors: K
authors: Urbahns
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SW7 3RP, UK.
authors: Julian
authors: J
authors: Blagg
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018360:Crystallography, X-Ray; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007191:Indazoles; D047428:Protein Kinase Inhibitors; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8
keywords: CDK19; CDK8; HSP90; Indazoles; Mediator complex; WNT pathway inhibitors