6MNY

Crystal structure of mouse BTK kinase domain in complex with compound 9a

6MNY の概要

• エントリーDOI: 10.2210/pdb6mny/pdb
• 分子名称: Tyrosine-protein kinase, 5-amino-1-[(3R)-1-cyanopiperidin-3-yl]-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole-4-carboxamide (3 entities in total)
• 機能のキーワード: kinase, drug design, transferase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64513.87

構造登録者

Han, S.,Caspers, N.,Ohren, J.O. (登録日: 2018-10-03, 公開日: 2019-01-30, 最終更新日: 2024-11-20)

主引用文献

Schnute, M.E.,Benoit, S.E.,Buchler, I.P.,Caspers, N.,Grapperhaus, M.L.,Han, S.,Hotchandani, R.,Huang, N.,Hughes, R.O.,Juba, B.M.,Kim, K.H.,Liu, E.,McCarthy, E.,Messing, D.,Miyashiro, J.S.,Mohan, S.,O'Connell, T.N.,Ohren, J.F.,Parikh, M.D.,Schmidt, M.,Selness, S.R.,Springer, J.R.,Thanabal, V.,Trujillo, J.I.,Walker, D.P.,Wan, Z.K.,Withka, J.M.,Wittwer, A.J.,Wood, N.L.,Xing, L.,Zapf, C.W.,Douhan III, J.
Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning.
ACS Med Chem Lett, 10:80-85, 2019

PubMed Abstract: Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

PubMed: 30655951
DOI: 10.1021/acsmedchemlett.8b00461

実験手法

X-RAY DIFFRACTION (2.8 Å)