1. Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit
- Author
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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, and Igor Mochalkin
- Subjects
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 - Abstract
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.
- Published
- 2018