Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit
| Autor: | Jared Head, Federica Morandi, Roland Grenningloh, Andreas Goutopoulos, Anna Gardberg, Lesley Liu-Bujalski, Constantin Neagu, Reinaldo Jones, Hui Qiu, Sherer Brian A, Johnson Theresa L, Richard D. Caldwell, Ariele Viacava Follis, Igor Mochalkin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine hemic and lymphatic diseases Drug Discovery Agammaglobulinaemia Tyrosine Kinase Bruton's tyrosine kinase Humans Kinome Molecular Biology Protein Kinase Inhibitors biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Active site Small molecule Cell biology 030104 developmental biology Protein kinase domain Covalent bond 030220 oncology & carcinogenesis Ibrutinib biology.protein Molecular Medicine Tyrosine kinase |
| Zdroj: | Bioorganicmedicinal chemistry letters. 28(17) |
| ISSN: | 1464-3405 |
| Popis: | Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR. |
| Databáze: | OpenAIRE |
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