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.
"To counteract the problem of resistance due to point mutations, several second-generation inhibitors have been synthesized and tested in pre-clinical assays: nilotinib (AMN107),8,16–18 dasatinib (BMS-354825),8,19–23 bosutinib,24 VX-680,21,25 AP23464,26,27 bafetinib,28,29 PD166326, PD180970 and PD173955,10,30–32 and ON012380.33 Two of them are currently being evaluated in phase II clinical trials – the dual-specificity Src/Abl inhibitor dasatinib and the imatinib derivative nilotinib. "
[Show abstract][Hide abstract] ABSTRACT: At present, there are no compounds in clinical development in the field of chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) that have been documented to harbor significant activity against the imatinib-resistant T315I mutation. Recent reports on the pre-clinical activity of some emerging tyrosine kinase inhibitors such as ON012380, VX-680 and PHA-739358 promise possible clinical efficacy against this specific Bcr-Abl mutant form. Here, we focus on the role of aurora kinase inhibitor VX-680 and PHA-739358 in blocking the leukemogenic pathways driven by wild-type and T315I-Bcr-Abl in CML or Ph+ ALL by reviewing recent research evidence. We also discuss the possibility of employing aurora kinase inhibitors as a promising new therapeutic approach in the treatment of CML and Ph+ ALL patients resistant to first and second generation TK inhibitors.
"Cell lines and reagents BV173, KT-1, KCL22, MYL, K562 and MEG-01 are cell lines derived from CML patients in blast crisis phase. Generation of multidrug resistant K562/D1-9, K562 subclones artificially overexpressing FLAG-tagged Bcl-2 (K562/Bcl-2) or Bcl-X L (K562/Bcl-X L ), transformed Ba/F3-derived haematopoietic cell lines Ba/F3/wt (bearing wild-type Bcr-Abl), Ba/F3/ E255K (mutated Bcr-Abl E255K ) and Ba/F3/T315I (Bcr-Ab- l T315I ) were described elsewhere (Urasaki et al, 1996; Kimura et al, 2005; Kuroda et al, 2006; Naito et al, 2006). IMresistant K562/IMR and MYL-R, expressing higher levels of Bcr-Abl protein, were generated by continuously exposing K562 and MYL, respectively, to 1 lmol/l IM (Ito et al, 2007). "
[Show abstract][Hide abstract] ABSTRACT: The effect of ABT-737, a BH3-mimicking inhibitor for anti-apoptotic Bcl-2 and Bcl-X(L), but not Mcl-1, against Bcr-Abl-positive (Bcr-Abl(+)) leukaemic cells was examined. ABT-737 potently induced apoptosis in Bcr-Abl(+) chronic myeloid leukaemia (CML) cell lines and primary CML samples in vitro and prolonged the survival of mice xenografted with BV173 cells, a CML cell line. Higher expression of anti-apoptotic Bcl-2 proteins reduced cell killing by ABT-737 in each cell line, but there was no correlation between the sensitivities to ABT-737 and the specific expression patterns of Bcl-2 family proteins among cell lines. Thus, the cell killing effect of ABT-737 must be determined not only by the expression patterns of Bcl-2 family proteins but also by other mechanisms, such as high expression of Bcr-Abl, or a drug-efflux pump, in CML cells. ABT-737 augmented the cell killing effect of imatinib in Bcr-Abl(+) cells with diverse drug-resistance mechanisms unless leukaemic cells harboured imatinib-insensitive Abl kinase domain mutations, such as T315I. The combination of homoharringtonine that reduces Mcl-1 enhanced the killing by ABT-737 strongly in Bcr-Abl(+) cells even with T315I mutation. These results suggest that ABT-737 is a useful component of chemotherapies for CML with diverse drug-resistance mechanisms.
British Journal of Haematology 02/2008; 140(2):181-90. DOI:10.1111/j.1365-2141.2007.06899.x · 4.71 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1007/s00280-006-0317-3 · 2.77 Impact Factor
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