7N4Q
Bruton's tyrosine kinase in complex with compound 45
Summary for 7N4Q
| Entry DOI | 10.2210/pdb7n4q/pdb |
| Descriptor | Tyrosine-protein kinase BTK, (2R)-2-(3-chloro-5-fluoroanilino)-2-cyclopropyl-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]acetamide (3 entities in total) |
| Functional Keywords | transferase, transferase inhibitor, kinase, kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 31871.00 |
| Authors | Metrick, C.M.,Marcotte, D.J. (deposition date: 2021-06-04, release date: 2022-05-18, Last modification date: 2023-10-18) |
| Primary citation | Hopkins, B.T.,Bame, E.,Bell, N.,Bohnert, T.,Bowden-Verhoek, J.K.,Bui, M.,Cancilla, M.T.,Conlon, P.,Cullen, P.,Erlanson, D.A.,Fan, J.,Fuchs-Knotts, T.,Hansen, S.,Heumann, S.,Jenkins, T.J.,Gua, C.,Liu, Y.,Liu, Y.,Lulla, M.,Marcotte, D.,Marx, I.,McDowell, B.,Mertsching, E.,Negrou, E.,Romanowski, M.J.,Scott, D.,Silvian, L.,Yang, W.,Zhong, M. Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel reversible Bruton's tyrosine kinase inhibitors. Bioorg.Med.Chem., 44:116275-116275, 2021 Cited by PubMed Abstract: Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization. PubMed: 34314938DOI: 10.1016/j.bmc.2021.116275 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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