In vivo antiproliferative effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on leukemic cells harbouring Abl kinase domain mutations.
ABSTRACT Advanced-phase chronic myeloid leukemia patients treated with imatinib often relapse due to point mutations in the Abl kinase domain. We herein examine the in vitro and in vivo effects of a Bcr-Abl/Lyn dual tyrosine kinase inhibitor, NS-187, on seven mutated Bcr-Abl proteins. NS-187 inhibited both Tyr393-phosphorylated and Tyr393-unphosphorylated Abl, resulting in significant in vitro growth inhibition of cells expressing six of seven mutated Bcr-Abl kinases, though not T315I. Furthermore, NS-187 prolonged the survival of mice injected with leukemic cells expressing all mutated Bcr-Abl tested except T315I, and its efficacy correlated well with its in vitro effects.
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ABSTRACT: Imatinib is widely recognized as the standard of care in the first-line treatment of chronic myeloid leukemia (CML); however, resistance can limit its long-term benefits. Early identification of the loss of response to imatinib is therefore important for the optimal management of patients with this type of leukemia. Cytogenetic and molecular responses during the first 12 months of treatment have been shown to predict future responses (complete cytogenetic response and major molecular response) and reduce disease progression. The degree of early reduction in BCR-ABL levels after commencing imatinib therapy is a good indicator of subsequent response. Monitoring for kinase domain mutations should also be considered in patients with suboptimal response or in those who demonstrate resistance. Modification of the treatment strategy is required if there is a loss of response. Dasatinib and nilotinib are the most extensively studied second-generation BCR-ABL tyrosine kinase inhibitors, and are currently approved for treating patients following imatinib failure.Clinical advances in hematology & oncology: H&O 10/2008; 6(9):673-83.
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ABSTRACT: Despite promising clinical results from imatinib mesylate and second-generation ABL tyrosine kinase inhibitors (TKIs) for most BCR-ABL(+) leukemia, BCR-ABL harboring the mutation of threonine 315 to isoleucine (BCR-ABL/T315I) is not targeted by any of these agents. We describe the in vitro and in vivo effects of AT9283 (1-cyclopropyl-3[5-morpholin-4yl methyl-1H-benzomidazol-2-yl]-urea), a potent inhibitor of several protein kinases, including Aurora A, Aurora B, Janus kinase 2 (JAK2), JAK3, and ABL on diverse imatinib-resistant BCR-ABL(+) cells. AT9283 showed potent antiproliferative activity on cells transformed by wild-type BCR-ABL and BCR-ABL/T315I. AT9283 inhibited proliferation in a panel of BaF3 and human BCR-ABL(+) cell lines both sensitive and resistant to imatinib because of a variety of mechanisms. In BCR-ABL(+) cells, we confirmed inhibition of substrates of both BCR-ABL (signal transducer and activator of transcription-5) and Aurora B (histone H3) at physiologically achievable concentrations. The in vivo effects of AT9283 were examined in several mouse models engrafted either subcutaneously or intravenously with BaF3/BCR-ABL, human BCR-ABL(+) cell lines, or primary patient samples expressing BCR-ABL/T315I or glutamic acid 255 to lysine, another imatinib-resistant mutation. These data together support further clinical investigation of AT9283 in patients with imatinib- and second-generation ABL TKI-resistant BCR-ABL(+) cells, including T315I.Blood 09/2010; 116(12):2089-95. · 9.78 Impact Factor
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ABSTRACT: Imatinib mesylate (Gleevec™) has improved the treatment of Bcr-Abl-positive leukemia. However, resistance is often reported in patients with advanced-stage disease. Chemical modifications of imatinib made with the guidance of molecular modeling have yielded several promising compounds that could override imatinib resistance. Among them, we selected a compound denoted NS-187. The most striking structural characteristic of NS-187 is its trifluoromethyl group at position 3 of the benzamide ring, which strengthens the hydrophobic interactions and fixes the conformation of the compound. NS-187 was 25–55 times more potent than imatinib against wild-type Bcr-Abl in vitro. At physiological concentrations, NS-187 also inhibited the phosphorylation and growth of all Bcr-Abl mutants tested except T315I. In addition to Bcr-Abl, NS-187 also inhibited Lyn, which might be involved in imatinib resistance, without affecting the phosphorylation of Src, Blk, or Yes. This indicates that NS-187 acts as a dual Bcr-Abl/Lyn inhibitor. Our proposed docking models of the NS-187/Abl complex support the notion that NS-187 is more specific for Lyn than for Src. In Balb/c-nu/nu mice, which were injected subcutaneously with Bcr-Abl-positive KU812 cells, NS-187 showed at least tenfold more potency than imatinib. We also tested the ability of NS-187 to suppress tumor growth in another murine tumor model, namely, Balb/c-nu/nu mice intravenously transplanted with BaF3 cells harboring wild-type or several mutations of Bcr-Abl (M244V, G250E, Q252H, Y253F, E255K, T315I, M351T, and H396P). NS-187 prolonged the survival of mice injected with leukemic cells expressing wild-type or all mutated Bcr-Abl except T315I, and its efficacy correlated well with its in vitro effects. NS-187 also inhibited leukemic cells harboring wild-type Bcr-Abl growth in the central nervous system, which sometimes becomes a sanctuary for leukemic cells under imatinib treatment. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Bcr-Abl-positive leukemia. A phase I study of NS-187 will start in 2006.Cancer Chemotherapy and Pharmacology 10/2006; 58:55-61. · 2.80 Impact Factor