6MNY

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

Summary for 6MNY

• Entry DOI: 10.2210/pdb6mny/pdb
• Descriptor: 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)
• Functional Keywords: kinase, drug design, transferase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 64513.87

Authors

Han, S.,Caspers, N.,Ohren, J.O. (deposition date: 2018-10-03, release date: 2019-01-30, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.8 Å)