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.