7LTY

Bruton's tyrosine kinase in complex with compound 23

7LTY の概要

• エントリーDOI: 10.2210/pdb7lty/pdb
• 関連するPDBエントリー: 6W07
• 分子名称: Isoform BTK-C of Tyrosine-protein kinase BTK, ~{N}-[(5~{R})-2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5~{H}-benzo[7]annulen-5-yl]-3-propan-2-yloxy-azetidine-1-carboxamide, DIMETHYL SULFOXIDE, ... (4 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: 31761.57

構造登録者

Metrick, C.M.,Marcotte, D.J. (登録日: 2021-02-20, 公開日: 2022-01-12, 最終更新日: 2023-10-18)

主引用文献

Hopkins, B.T.,Bame, E.,Bajrami, B.,Black, C.,Bohnert, T.,Boiselle, C.,Burdette, D.,Burns, J.C.,Delva, L.,Donaldson, D.,Grater, R.,Gu, C.,Hoemberger, M.,Johnson, J.,Kapadnis, S.,King, K.,Lulla, M.,Ma, B.,Marx, I.,Magee, T.,Meissner, R.,Metrick, C.M.,Mingueneau, M.,Murugan, P.,Otipoby, K.L.,Polack, E.,Poreci, U.,Prince, R.,Roach, A.M.,Rowbottom, C.,Santoro, J.C.,Schroeder, P.,Tang, H.,Tien, E.,Zhang, F.,Lyssikatos, J.
Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis.
J.Med.Chem., 65:1206-1224, 2022

PubMed Abstract: Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091, a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclinical studies demonstrated BIB091 to be a high potency molecule with good drug-like properties and a safety/tolerability profile suitable for clinical development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.

PubMed: 34734694
DOI: 10.1021/acs.jmedchem.1c00926

実験手法

X-RAY DIFFRACTION (1.69 Å)