Discovery of BIIB068: A Selective, Potent, Reversible Bruton’s Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases
| Autor: | Kevin L. Otipoby, Sarah Sheikh, Douglas Marcotte, George A. Moniz, Michael Humora, Brian T. Hopkins, Judy Bai, Karen Smirnakis, J. Michael Macphee, Tonika Bohnert, Timothy R. Chan, Devangi Mehta, Bin Ma, Million Arefayene, Zheng Fengmei, Lei Zhang, Patricia Schroeder, Annick Prefontaine, Eris Bame, Urjana Poreci, Evelyne Polack, Eric Tien, Claire M. Metrick, Bekim Bajrami |
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| Rok vydání: | 2020 |
| Předmět: |
Drug Evaluation
Preclinical Administration Oral Molecular Dynamics Simulation Pharmacology 01 natural sciences Autoimmune Diseases Mice Structure-Activity Relationship 03 medical and health sciences Dogs Immune system immune system diseases Catalytic Domain hemic and lymphatic diseases Drug Discovery Agammaglobulinaemia Tyrosine Kinase Animals Humans Bruton's tyrosine kinase Kinome Kinase activity Receptor Protein Kinase Inhibitors 030304 developmental biology 0303 health sciences Binding Sites biology Chemistry Antigens T-Independent Rats 0104 chemical sciences 010404 medicinal & biomolecular chemistry Pyrimidines Microsomes Liver biology.protein Molecular Medicine Phosphorylation Female Antibody Tyrosine kinase Half-Life |
| Zdroj: | Journal of Medicinal Chemistry. 63:12526-12541 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c00702 |
| Popis: | Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans. |
| Databáze: | OpenAIRE |
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