4OTR

Crystal structure of BTK kinase domain complexed with 6-cyclopropyl-2-[3-[5-[[5-(4-ethylpiperazin-1-yl)-2-pyridyl]amino]-1-methyl-6-oxo-3-pyridyl]-2-(hydroxymethyl)phenyl]-8-fluoro-isoquinolin-1-one

Summary for 4OTR

• Entry DOI: 10.2210/pdb4otr/pdb
• Related: 4OT5 4OT6 4OTQ
• Descriptor: Tyrosine-protein kinase BTK, 6-cyclopropyl-2-[3-(5-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl]-8-fluoroisoquinolin-1(2H)-one, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33298.12

Authors

Kuglstatter, A.,Wong, A. (deposition date: 2014-02-14, release date: 2014-05-14, Last modification date: 2023-09-20)

Primary citation

Lou, Y.,Han, X.,Kuglstatter, A.,Kondru, R.K.,Sweeney, Z.K.,Soth, M.,McIntosh, J.,Litman, R.,Suh, J.,Kocer, B.,Davis, D.,Park, J.,Frauchiger, S.,Dewdney, N.,Zecic, H.,Taygerly, J.P.,Sarma, K.,Hong, J.,Hill, R.J.,Gabriel, T.,Goldstein, D.M.,Owens, T.D.
Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis.
J.Med.Chem., 58:512-516, 2015

PubMed Abstract: Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.

PubMed: 24712864
DOI: 10.1021/jm500305p

Experimental method

X-RAY DIFFRACTION (1.95 Å)