Structural highlights
Publication Abstract from PubMed
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.
Rational design of highly selective spleen tyrosine kinase inhibitors.,Lucas MC, Goldstein DM, Hermann JC, Kuglstatter A, Liu W, Luk KC, Padilla F, Slade M, Villasenor AG, Wanner J, Xie W, Zhang X, Liao C J Med Chem. 2012 Dec 13;55(23):10414-23. doi: 10.1021/jm301367c. Epub 2012 Nov, 27. PMID:23151054[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lucas MC, Goldstein DM, Hermann JC, Kuglstatter A, Liu W, Luk KC, Padilla F, Slade M, Villasenor AG, Wanner J, Xie W, Zhang X, Liao C. Rational design of highly selective spleen tyrosine kinase inhibitors. J Med Chem. 2012 Dec 13;55(23):10414-23. doi: 10.1021/jm301367c. Epub 2012 Nov, 27. PMID:23151054 doi:http://dx.doi.org/10.1021/jm301367c
