8E2M

Bruton's tyrosine kinase (BTK) with compound 13

8E2M の概要

• エントリーDOI: 10.2210/pdb8e2m/pdb
• 分子名称: Tyrosine-protein kinase BTK, (5P)-5-[4-methyl-6-(2-methylpropyl)pyridin-3-yl]-4-oxo-N-[(1R,2S)-2-propanamidocyclopentyl]-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide, TRIETHYLENE GLYCOL, ... (4 entities in total)
• 機能のキーワード: protein kinase, inhibitor, covalent, transferase-transferase inhibitor complex, transferase
• 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: 32269.11

構造登録者

Alexander, R.,Milligan, C.M. (登録日: 2022-08-15, 公開日: 2022-11-16, 最終更新日: 2024-10-16)

主引用文献

Tichenor, M.S.,Wiener, J.J.M.,Rao, N.L.,Bacani, G.M.,Wei, J.,Pooley Deckhut, C.,Barbay, J.K.,Kreutter, K.D.,Chang, L.,Clancy, K.W.,Murrey, H.E.,Wang, W.,Ahn, K.,Huber, M.,Rex, E.,Coe, K.J.,Wu, J.,Rui, H.,Sepassi, K.,Gaudiano, M.,Bekkers, M.,Cornelissen, I.,Packman, K.,Seierstad, M.,Xiouras, C.,Bembenek, S.D.,Alexander, R.,Milligan, C.,Balasubramanian, S.,Lebsack, A.D.,Venable, J.D.,Philippar, U.,Edwards, J.P.,Hirst, G.
Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
J.Med.Chem., 65:14326-14336, 2022

PubMed Abstract: Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

PubMed: 36314537
DOI: 10.1021/acs.jmedchem.2c01026

実験手法

X-RAY DIFFRACTION (1.904 Å)