7N4S

Bruton's tyrosine kinase in complex with compound 65

7N4S の概要

• エントリーDOI: 10.2210/pdb7n4s/pdb
• 関連するPDBエントリー: 7N4Q 7N4R
• 分子名称: Tyrosine-protein kinase BTK, (3R,3'R)-3-anilino-1'-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)[1,3'-bipiperidin]-2-one (3 entities in total)
• 機能のキーワード: transferase, transferase inhibitor, kinase, kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31818.56

構造登録者

Metrick, C.M.,Marcotte, D.J. (登録日: 2021-06-04, 公開日: 2022-05-18, 最終更新日: 2023-10-18)

主引用文献

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

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: 34314938
DOI: 10.1016/j.bmc.2021.116275

実験手法

X-RAY DIFFRACTION (2.05 Å)