5FBN

BTK kinase domain with inhibitor 1

Summary for 5FBN

• Entry DOI: 10.2210/pdb5fbn/pdb
• Descriptor: Tyrosine-protein kinase BTK, 4-[8-azanyl-3-[(3~{R})-1-(3-methyloxetan-3-yl)carbonylpiperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl]-~{N}-[4-(trifluoromethyl)pyridin-2-yl]benzamide, 4-[8-azanyl-3-[(2~{S})-1-[4-(dimethylamino)butanoyl]pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-~{N}-(1,3-thiazol-2-yl)benzamide, ... (6 entities in total)
• Functional Keywords: kinase, phosphatase, transferase-transferase inhibitor complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 66563.23

Authors

Raaijmakers, H.C.A.,Vu-Pham, D. (deposition date: 2015-12-14, release date: 2016-02-03, Last modification date: 2024-05-01)

Primary citation

Liu, J.,Guiadeen, D.,Krikorian, A.,Gao, X.,Wang, J.,Boga, S.B.,Alhassan, A.B.,Yu, Y.,Vaccaro, H.,Liu, S.,Yang, C.,Wu, H.,Cooper, A.,de Man, J.,Kaptein, A.,Maloney, K.,Hornak, V.,Gao, Y.D.,Fischmann, T.O.,Raaijmakers, H.,Vu-Pham, D.,Presland, J.,Mansueto, M.,Xu, Z.,Leccese, E.,Zhang-Hoover, J.,Knemeyer, I.,Garlisi, C.G.,Bays, N.,Stivers, P.,Brandish, P.E.,Hicks, A.,Kim, R.,Kozlowski, J.A.
Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.
Acs Med.Chem.Lett., 7:198-203, 2016

PubMed Abstract: Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.

PubMed: 26985298
DOI: 10.1021/acsmedchemlett.5b00463

Experimental method

X-RAY DIFFRACTION (1.8 Å)