4FYO

Crystal structure of spleen tyrosine kinase complexed with N-{(S)-1-[7-(3,4-Dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-pyrrolidin-3-yl}-terephthalamic acid

Summary for 4FYO

• Entry DOI: 10.2210/pdb4fyo/pdb
• Related: 4FYN
• Descriptor: Tyrosine-protein kinase SYK, 4-{[(3S)-1-{7-[(3,4-dimethoxyphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}pyrrolidin-3-yl]carbamoyl}benzoic acid (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: 34404.56

Authors

Kuglstatter, A.,Slade, M. (deposition date: 2012-07-05, release date: 2013-01-30, Last modification date: 2023-09-13)

Primary citation

Lucas, M.C.,Goldstein, D.M.,Hermann, J.C.,Kuglstatter, A.,Liu, W.,Luk, K.C.,Padilla, F.,Slade, M.,Villasenor, A.G.,Wanner, J.,Xie, W.,Zhang, X.,Liao, C.
Rational design of highly selective spleen tyrosine kinase inhibitors.
J.Med.Chem., 55:10414-10423, 2012

PubMed Abstract: A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.

PubMed: 23151054
DOI: 10.1021/jm301367c

Experimental method

X-RAY DIFFRACTION (1.4 Å)