auto phosphorylation of Bcr-Abl on Tyr-177 that is involved in CML pathogenesis. Synergistic activity of imatinib and nilotinib has been reported following coadministration. This might be a result of the fact that the drugs are taken up in cells by different mechanisms: imatinib influx is dependent on OCT1 but nilotinib is not. Nilotinib is also not a substrate for the efflux transporter P-glycoprotein pump, unlike imatinib. Although the two dimensional molecular structures of these two drugs might look similar, they are dissimilar in terms of spatial structure and molecular properties. Binding Nilotinib binds to the inactive conformation of the Abl kinase domain, largely through lipophilic interactions and thus blocks its catalytic activity. Nilotinib binds to the kinase domain by making four hydrogen bond interactions involving the pyridyl-N and the backbone NH of Met-318, the anilino-NH and the side chain OH of Thr-315, the amido-NH and side chain carboxylate of Glu-286 and the amido carbonyl with the backbone NH of the Asp-381. The [4-(3-pyridinyl)-2-pyrimidinyl] anilino segment of nilotinib has close binding interactions with Met-318, Phe-317 and Thr-315 residues of a region within the ATP binding site. The remaining half of the compound extends beyond the Thr-315 gatekeeper residue to bind within an additional pocket. The 3-methylimidazole and trifluoro-methyl groups of nilotinib make important interactions with the Abl kinase domain. These groups also make the shape of nilotinib very different from that of imatinib. Nilotinib also binds to the kinase through a large number of weak van der Waals interactions. Resistance Nilotinib has shown effect against most mutations (32/33) that are associated with imatinib resistance but the T315I mutant remains resistant to nilotinib. Its ineffectiveness against the T315I mutant seems to be a consequence of the loss of an H-bond interaction between threonine-O and aniline-NH on nilotinib and a steric clash between the isoleucine-methyl group and 2-methylphenyl phenyl group of nilotinib. On the other hand, resistance to nilotinib is associated with a limited spectrum of Bcr-Abl kinase mutations that mostly affect the P-loop and T315I. However all mutations except T315I were effectively suppressed by increasing nilotinib concentration. Although nilotinib is more potent than imatinib it is possible that its specific mode of binding to Abl may make other sites vulnerable to new kinds of drug resistance. Dasatinib (BMS-354825) Development Dasatinib is a thiazolylaminopyrimidine developed as the hydrochloride salt. It was discovered with a program directed towards immunosuppressive drugs and is 325-fold more