6TFP
BTK in complex with LOU064, a potent and highly selective covalent inhibitor
Summary for 6TFP
| Entry DOI | 10.2210/pdb6tfp/pdb |
| Descriptor | Tyrosine-protein kinase BTK, SODIUM ION, ~{N}-[3-[6-azanyl-5-[2-[methyl(propanoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoranyl-2-methyl-phenyl]-4-cyclopropyl-2-fluoranyl-benzamide, ... (4 entities in total) |
| Functional Keywords | btk, complex, inhibitor, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 5 |
| Total formula weight | 162652.30 |
| Authors | Scheufler, C.,Hinniger, A.,Gutmann, S. (deposition date: 2019-11-14, release date: 2020-03-04, Last modification date: 2024-11-06) |
| Primary citation | Angst, D.,Gessier, F.,Janser, P.,Vulpetti, A.,Walchli, R.,Beerli, C.,Littlewood-Evans, A.,Dawson, J.,Nuesslein-Hildesheim, B.,Wieczorek, G.,Gutmann, S.,Scheufler, C.,Hinniger, A.,Zimmerlin, A.,Funhoff, E.G.,Pulz, R.,Cenni, B. Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase. J.Med.Chem., 63:5102-5118, 2020 Cited by PubMed Abstract: Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, ), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent target occupancy with an EC of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren's syndrome. PubMed: 32083858DOI: 10.1021/acs.jmedchem.9b01916 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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