binds to a pocket induced by the inactive conformation kinase. Also in the conformation of the kinase that ponatinib rests in, additional favorable van der Waals interactions between the drug and Tyr-253 and Phe-382. Five hydrogen bonds are generated, with the backbone of Met-318 in the hinge region, with the backbone of Asp-381, with the side chain of Glu-286 and the protonated methylpiperazine with the backbone-carbonyl atoms of Ile-360 and His-361. With this structure ponatinib has been shown to have a relatively broad kinase specificity profile which can probably be linked to the linearity of the linkage section of the molecule. With this linear structure the drug appears to avoid steric clashes with hydrophobic TK gatekeeper residues. Despite, or even because of this, ponatinib is a potent drug and targets not just most of the known mutations on the Bcr-Abl TK but, most importantly of all, T315I. This mutation is emerging as a common pathway to failure of both first and second line treatments. Unlike other T315I targeting inhibitors in development, ponatinib does not target Aurora kinases, which clearly distinguishes it from them and emphasizes the significance of its discovery. Bafetinib (INNO-406) With the emerging resistance to imatinib treatment after its launch alternative treatment was highly sought after. Bafetinib was the offspring of an attempt to create a more potent drug than imatinib, with efficacy against various point mutations in the Bcr-Abl kinase, with fewer adverse effects and with narrower kinase spectra, namely just Lyn and Bcr-Abl. Development In the search for a substance that fit the criteria mentioned, the crystal structure of imatinib bound to Abl was examined. This revealed a hydrophobic pocket around the phenyl ring adjacent to the piperazinylmethyl group of imatinib. Attempts to utilize this pocket to increase efficacy led to the addition of various hydrophobic groups including single fluoro, bromo and chloro substituents. Finally a trifluoromethyl group at position 3 was found to give the best results, with approximately 36-fold improvement over imatinib. The addition of a hydrophobic group now needed to be countered to sustain the solubility of the substance. Closer examination of the crystal structure of imatinib-kinase complex revealed Tyr-236 was in close proximity to the pyridine ring of imatinib, suggesting there was little or no room for a larger group there. With that in mind a more hydrophilic pyrimidine ring was substituted for the pyridine, which was found to increase solubility while