potent against cells expressing wild type Bcr-Abl than imatinib. Dasatinib is a multi targeted inhibitor of Bcr-Abl and Src family kinases. It also has inhibitory activity against additional downstream kinases. Binding Dasatinib binds to Abl with less stringent conformational requirements than imatinib so it exhibits increased potency but reduced selectivity compared to imatinib. Dasatinib binds both the active and inactive conformation of Abl kinase, contrary to the binding of most other TKIs to the active form only. Compounds that target the active conformation have been identified but the binding site in all the hundreds of human protein kinases is very similar. Therefore, there is a considerably greater scope for dissimilarities between the inactive conformations so the efforts to discover highly selective kinase inhibitors are being directed towards molecules that bind to the inactive conformation. Dasatinib has some structural elements in common with nilotinib, in particular the juxtaposition of the aminopyrimidine and the carboxamide groups. The aminothiazole segment of dasatinib makes a bi-dentate H-bonding interaction with the backbone CO and NH of Met-318 and the amide-NH makes an H-bond with the side chain oxygen of Thr-315. Resistance Since dasatinib is an inhibitor of Src family kinases, it can overcome resistance due to Src family kinase activation. Because it does not bind to Bcr-Abl with the same stringent conformational requirements as imatinib, it can inhibit all Bcr-Abl kinase domain mutants except for T315I. Dasatinib is also not a substrate of multidrug P-glycoprotein efflux pumps like imatinib. Because of this dasatinib may be active in some patients after failure with both imatinib and nilotinib. Although dasatinib is much more potent than imatinib it is possible, like with nilotinib, that its specific mode of binding to Abl may lead to new vulnerable sites that could confer new kinds of drug resistance. Mutations have been found on Phe317 so that is a potential vulnerable site for this drug. Bosutinib (SKI-606) Development Bosutinib's structure is based on a quinoline scaffold and is structurally related to the AstraZeneca quinazoline template. Src kinase dependent yeast screening led to characterization of a 4-anilino-3-quinolinecarbonitrile as an Src inhibitor. Combination of the features of this hit and a related compound, and attachment of solubilizing groups, led to the discovery of bosutinib. It was suggested to be an Abl kinase inhibitor and when tested as such it turned out to be slightly more potent against Abl than Src (IC50 1,4 nM vs.