4NWM

Crystal structure of Bruton agammaglobulinemia tyrosine kinase complexed with BMS-809959 aka 4-tert-butyl-n-[2-me thyl-3-(6-{[4-(morpholine-4-carbonyl)phenyl]amino}-9h- purin-2-yl)phenyl]benzamide

Summary for 4NWM

• Entry DOI: 10.2210/pdb4nwm/pdb
• Descriptor: Tyrosine-protein kinase BTK, 4-tert-butyl-N-[2-methyl-3-(6-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-7H-purin-2-yl)phenyl]benzamide (3 entities in total)
• Functional Keywords: kinase, btk, atk, xla, psctk1, agmx1, at, imd1, mgc126261, mgc126262 bpk, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q06187
• Total number of polymer chains: 2
• Total formula weight: 62860.40

Authors

Muckelbauer, J.K. (deposition date: 2013-12-06, release date: 2014-04-02, Last modification date: 2025-03-26)

Primary citation

Shi, Q.,Tebben, A.,Dyckman, A.J.,Li, H.,Liu, C.,Lin, J.,Spergel, S.,Burke, J.R.,McIntyre, K.W.,Olini, G.C.,Strnad, J.,Surti, N.,Muckelbauer, J.K.,Chang, C.,An, Y.,Cheng, L.,Ruan, Q.,Leftheris, K.,Carter, P.H.,Tino, J.,De Lucca, G.V.
Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases.
Bioorg.Med.Chem.Lett., 24:2206-2211, 2014

PubMed Abstract: Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.

PubMed: 24685542
DOI: 10.1016/j.bmcl.2014.02.075

Experimental method

X-RAY DIFFRACTION (2.03 Å)