4FZ7

Crystal structure of spleen tyrosine kinase complexed with 6-((1R,2S)-2-Amino-cyclohexylamino)-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide

Summary for 4FZ7

• Entry DOI: 10.2210/pdb4fz7/pdb
• Related: 3FQE
• Descriptor: Tyrosine-protein kinase SYK, 6-{[(1R,2S)-2-aminocyclohexyl]amino}-4-[(6-ethylpyridin-2-yl)amino]pyridazine-3-carboxamide (3 entities in total)
• Functional Keywords: kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34239.44

Authors

Kuglstatter, A.,Slade, M. (deposition date: 2012-07-06, release date: 2013-07-10, Last modification date: 2023-09-13)

Primary citation

Lucas, M.C.,Bhagirath, N.,Chiao, E.,Goldstein, D.M.,Hermann, J.C.,Hsu, P.Y.,Kirchner, S.,Kennedy-Smith, J.J.,Kuglstatter, A.,Lukacs, C.,Menke, J.,Niu, L.,Padilla, F.,Peng, Y.,Polonchuk, L.,Railkar, A.,Slade, M.,Soth, M.,Xu, D.,Yadava, P.,Yee, C.,Zhou, M.,Liao, C.
Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.
J. Med. Chem., 57:2683-2691, 2014

PubMed Abstract: Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.

PubMed: 24520947
DOI: 10.1021/jm401982j

Experimental method

X-RAY DIFFRACTION (1.75 Å)