Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening
| العنوان: | Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening |
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| المؤلفون: | Djordje Musil, Suzanne A. Eccles, Daniel Schwarz, Klaus Urbahns, Trevor Clive Dale, Paul A. Clarke, Christina Esdar, Paul Czodrowski, Maria-Jesus Ortiz-Ruiz, Oliver Pöschke, Florence I. Raynaud, Aurélie Mallinger, Dirk Wienke, Kai Schiemann, Richard Schneider, Felix Rohdich, Michael Busch, Julian Blagg |
| المصدر: | Journal of Medicinal Chemistry. 59:9337-9349 |
| بيانات النشر: | American Chemical Society (ACS), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, High-throughput screening, Mice, Nude, Antineoplastic Agents, Pharmacology, Mice, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Cyclin-dependent kinase, Thiadiazoles, Drug Discovery, Biomarkers, Tumor, Animals, Humans, Structure–activity relationship, Protein Kinase Inhibitors, Cell Proliferation, Dose-Response Relationship, Drug, Molecular Structure, Oncogene, biology, Drug discovery, Kinase, Chemistry, Imidazoles, Wnt signaling pathway, Neoplasms, Experimental, Cyclin-Dependent Kinase 8, High-Throughput Screening Assays, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, Cyclin-dependent kinase 8, Female, Drug Screening Assays, Antitumor |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2ecdf42911d63ceaf78c9765d5396808 https://doi.org/10.1021/acs.jmedchem.6b00597 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....2ecdf42911d63ceaf78c9765d5396808 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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