Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile
| Autor: | Petro Halkowycz, Douglas R. Dougan, Simone V. Bigi-Botterill, Derek C. Cole, Ben Johnson, Erica L. Bradshaw, Christopher McBride, Mark Sabat, Steven Swann, Anthony Ivetac, Jacques Ermolieff, Jason Pickens |
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| Rok vydání: | 2020 |
| Předmět: |
MAP kinase kinase kinase
010405 organic chemistry Kinase p38 mitogen-activated protein kinases Organic Chemistry Clinical Biochemistry Pharmaceutical Science computer.file_format Protein Data Bank 01 natural sciences Biochemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry Drug Discovery Biophysics Molecular Medicine Kinome ASK1 Protein kinase A Molecular Biology computer Lead compound |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 30:127405 |
| ISSN: | 0960-894X |
| Popis: | Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd 5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series. |
| Databáze: | OpenAIRE |
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