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Imatinib (Gleevec®, Novartis Pharma AG) is an effective first line therapy for CML, although in advanced stage CML and Ph+ ALL, but relapse can occur due to the development of resistance. Relapse often results from the clonal expansion of cells expressing Bcr-Abl kinase domain mutants, which are resistant to inhibition by imatinib. Utilising the crystal structure of the Abl-imatinib complex, AMN107 (4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide) was designed as more potent and highly selective inhibitor of Bcr-Abl tyrosine kinase. AMN107 reduces the cellular Bcr-Abl autophosphorylation and the proliferation of Ba/F3 Bcr-Abl cells with a mean IC50 values of 21 and 25 nM, respectively (Imatinib: 220 and 649 nM). In addition to inhibiting the non-mutated enzyme, AMN107 potently inhibits the Bcr-Abl activity of many imatinib-resistant mutants in transfected Ba/F3 cells (mean autophosphorylation / mean proliferation IC50; nM): G250E (n.d. / 54), E255K (150 / 566), E255V (246 / 681), E292K (31 / 94), F317L (41 / 80), M351T (31 / 33) and F486S (43 / 87), but does not inhibit the T315I mutant. Like imatinib, AMN107 also inhibits the c-Kit and PDGFR receptor kinases, with mean anti-proliferative IC50 values of 160 nM (exon13 mutant Kit expressing GIST cells), 26 nM (del 560-561 expressing Ba/F3 cells), 3.5 nM (FIPL1-PDGFRα expressing Ba/F3 cells) and 57 nM (Tel-PDGFRβ expressing Ba/F3 cells). As in the case of T315I Bcr-Abl mutant, the corresponding FIPL1-T674I-PDGFRα gatekeeper mutant is less sensitive to AMN107 (IC50 1340 nM). AMN107 shows an attractive kinase selectivity profile, having no effect on the viability of Ba/F3 cell lines engineered to express a panel of other receptor and non-receptor tyrosinse kinases, or on parental Ba/F3 cells grown in the presence of IL-3. AMN107 shows a good pharmacokinetic profile is well tolerated in rodents and dogs, and represents a promising new Bcr-Abl tyrosine kinase inhibitor which is currently undergoing evaluation in Phase I clinical trials.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]