Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.
View/ Open
Date
2016-10-27Author
Czodrowski, P
Mallinger, A
Wienke, D
Esdar, C
Pöschke, O
Busch, M
Rohdich, F
Eccles, SA
Ortiz-Ruiz, M-J
Schneider, R
Raynaud, FI
Clarke, PA
Musil, D
Schwarz, D
Dale, T
Urbahns, K
Blagg, J
Schiemann, K
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Humans
Mice
Mice, Nude
Neoplasms, Experimental
Imidazoles
Thiadiazoles
Antineoplastic Agents
Protein Kinase Inhibitors
Drug Screening Assays, Antitumor
Cell Proliferation
Molecular Structure
Structure-Activity Relationship
Dose-Response Relationship, Drug
Female
Drug Discovery
Cyclin-Dependent Kinase 8
High-Throughput Screening Assays
Biomarkers, Tumor
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology
Language
eng
Date accepted
2016-08-05
License start date
2016-10-07
Citation
Journal of medicinal chemistry, 2016, 59 (20), pp. 9337 - 9349
Publisher
AMER CHEMICAL SOC