first Bcr-Abl tyrosine kinase inhibitor to be used in the treatment of CML. Development In the development of imatinib, the structure of Bcr-Abl tyrosine kinase played a limited role because it was unknown. A high-throughput screening of chemical libraries at Novartis was performed to identify a starting molecule, which was called "Pyrimidine A". This compound served as a lead compound and was then tested and modified to develop imatinib. With a replacement of the imidazole group with a benzamido group, the compound's specificity increased while its activity as a kinase inhibitor remained the same. Subsequently, introducing a methyl substituent ortho to the pyrimidinyl-amino group enhanced the potency. Binding Since then crystallographic studies have revealed that imatinib binds to the kinase domain of Abl only when the domain adopts the inactive or "closed" conformation. This is where the glycine-rich, P-binding phosphate loop (P-loop) folds over the ATP binding site and the activation-loop adopts a conformation in which it occludes the substrate binding site and disrupts the ATP phosphate binding site to block the catalytic activity of the enzyme. The shift of the AspPheGly (DFG) triad at the N-terminal end of the activation loop results in the exposure of a binding pocket which can be utilized by inhibitors. This conformation is referred to as DFGout. Imatinib binds to Abl domain via six hydrogen bond interactions. This stabilizes the imatinib Bcr-Abl complex and prevents ATP from reaching its binding site. The hydrogen bonds involve the pyridine-N and backbone-NH of Met-318, the aminopyrimidine and side chain hydroxyl of Thr-315, the amide-NH and side chain carboxylate of Glu-286, the carbonyl and backbone-NH of Asp-381, the protonated methylpiperazine with the backbone-carbonyl atoms of Ile-360 and His-361. Additionally, a number of van der Waals interactions contribute to binding. A hydrophobic pocket is formed by amino acid residues Ile-293, Leu-298, Leu-354 and Val-379 around the phenyl ring adjacent to the piperazinyl-methyl group of imatinib. At the time of its discovery, in the absence of structural information, no clear explanation for the impressive selectivity of imatinib could be found. Although first-generation treatment achieved an extremely high response rate and a low relapse rate in CML patients, some patients do experience resistance or intolerance to imatinib. Drug resistance Drug resistance is the main drive in continuing research and development of Bcr-Abl TKI. Shortly after the introduction of imatinib, investigators began to describe a number of in vitro derived cell lines