Progress in the Discovery of BCR-ABL Kinase Inhibitors for the Treatment of Leukemia

Investigations into the Potential Role of Metabolites on the Anti-Leukemic Activity of Imatinib, Nilotinib and Midostaurin

“…The crystal structure of nilotinib in complex with human ABL1 kinase confirms that the drug binds in a similar manner to that of imatinib, with the activation-loop adopting a 'DFG-out' inactive conformation. [8,11] Whereas the hydrogen-bond interactions involving the pyridyl-N with the backbone-NH of Met318, the anilino-NH with the side-chain hydroxyl of Thr315, and the pyrimidine-N atom with the conserved water molecule are observed in both structures, there are some major differences in the other molecular interactions through which the drugs bind (Fig. 1b).…”

“…[7] The latter activity underlies the efficacy of imatinib as a therapy for chronic myeloid leukaemia (CML), which when adequately treated has now been transformed into a chronic disease. [8] Following ground-breaking findings from the Kuriyan group, [9] it has been established that imatinib inhibits the kinase activity of ABL1 by binding in a so-called 'type-2' fashion to a 'DFG-out' catalytically inactive conformation of the kinase domain, thereby preventing AT P from binding. [8][9][10][11][12] The imatinib-ABL1 complex is stabilised by a large number of van der Waal's contacts which play a major part in driving the binding energy, supplemented by an array of hydrogen bonds that define the geometry of the interactions.…”

“…[8] Following ground-breaking findings from the Kuriyan group, [9] it has been established that imatinib inhibits the kinase activity of ABL1 by binding in a so-called 'type-2' fashion to a 'DFG-out' catalytically inactive conformation of the kinase domain, thereby preventing AT P from binding. [8][9][10][11][12] The imatinib-ABL1 complex is stabilised by a large number of van der Waal's contacts which play a major part in driving the binding energy, supplemented by an array of hydrogen bonds that define the geometry of the interactions. The latter involve the pyridine-N and backbone-NH of Met318, the aminopyrimidine and side-chain hydroxyl of Thr315, the amide-NH and side-chain carboxylate of Glu286, the amide-carbonyl and backbone-NH of Asp381, together with the protonated methylpiperazine with the backbone-carbonyl atoms of Ile360 and His361 (Fig.…”

“…Structure-guided medicinal chemistry directed towards finding a drug that would address imatinib-resistance in CML patients culminated in the discovery of nilotinib (11; Tasigna ® ). [8,11,30] Although nilotinib has similar potency to imatinib towards the DDR, PDGFR and KIT receptor kinases, it is much more potent and hence selective towards ABL1/BCR-ABL1. [7,28] This activity translates into nilotinib being able to combat imatinib resistance in CML patients, as well as it having superior efficacy in newly-diagnosed patients.…”

“…[7,28] This activity translates into nilotinib being able to combat imatinib resistance in CML patients, as well as it having superior efficacy in newly-diagnosed patients. [8] In addition to being designed to have a much better topological fit to the binding pocket identified from the imatinib-ABL1 crystal structure, nilotinib was constructed to avoid any liability of amide cleavage leading to the formation of the mutagenic phenylenediamine 9 and to have lowered basicity, thus reducing its potential to be a good substrate for cell efflux pump transporters. The crystal structure of nilotinib in complex with human ABL1 kinase confirms that the drug binds in a similar manner to that of imatinib, with the activation-loop adopting a 'DFG-out' inactive conformation.…”