Spleen tyrosine kinase is a non-receptor tyrosine kinase, overactivation of which is thought to contribute to autoimmune diseases as well as allergy and asthma. Protein kinases have a highly conserved ATP binding site, thus making challenging the design of selective small molecule inhibitors. It has been well documented that some protein kinases can be stabilized in their inactive conformations (Type-II inhibitors). Herein, we describe a protein structure/ligand-based approach to successfully identify ligands that bind to novel conformations of spleen tyrosine kinase. By utilizing kinase protein crystal structures both in the public domain (RCSB) and within Pfizer’s protein crystal database, we report the discovery of the first spleen tyrosine kinase Type-II ligands. Compounds 1 and 3 were found to bind to the DFG-out conformation of spleen tyrosine kinase, while compound 2 binds to a DFG-in, C-Helix-out conformation. In this instance, the C-helix moved significantly to create a large hydrophobic pocket rarely seen in kinase protein crystal structures.