Discovery of potent,highly selective covalent irreversible BTK inhibitors from a fragment hit |
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Authors: | Hui Qiu Lesley Liu-Bujalski Richard D Caldwell Ariele Viacava Follis Anna Gardberg Andreas Goutopoulos Roland Grenningloh Jared Head Theresa Johnson Reinaldo Jones Igor Mochalkin Federica Morandi Constantin Neagu Brian Sherer |
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Affiliation: | 1. EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA;2. Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, USA;3. F. Hoffmann-La Roche AG, Konzern-Hauptsitz, Grenzacherstrasse 124, CH-4070 Basel, Switzerland |
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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. |
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Keywords: | Covalent Irreversible BTK inhibitor Fragment |
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