NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia.

@article{Kimura2005NS187AP,
  title={NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia.},
  author={Shinya Kimura and Haruna Naito and Hidekazu Segawa and Junya Kuroda and Takeshi Yuasa and Kiyoshi Sato and Asumi Yokota and Yuri Kamitsuji and Eri Kawata and Eishi Ashihara and Yohei Nakaya and Haruna Naruoka and Tatsushi Wakayama and Kimio Nasu and Tetsuo Asaki and Tomoko Niwa and Kazuko Hirabayashi and Taira Maekawa},
  journal={Blood},
  year={2005},
  volume={106 12},
  pages={
          3948-54
        }
}
Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187… 

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Development of NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor

NS-187 was 25–55 times more potent than imatinib against wild-type Bcr-Abl in vitro and the proposed docking models of the NS-187/Abl complex support the notion that NS- 187 is more specific for Lyn than for Src, and suggest that it may be a potentially valuable novel agent to combat imatinIB-resistant Bcr -Abl-positive leukemia.

Bcr-Abl Kinase Inhibitors

The progress made on the development of thesenew agents, including compounds with activity against the highly resistant T315I mutation of Bcr-Abl, will be discussed.

The Second Generation of BCR-ABL Tyrosine Kinase Inhibitors

The need for alternative or additional treatment for imatinib-resistant BCR-ABL-positive leukemia has guided the way to the design of a second generation of targeted therapies, which has resulted mainly in the development of novel small-molecule inhibitors such as AMN107, dasatinib, NS-187, and ON012380.

Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells.

In vitro and in vivo results support further clinical investigation of AT9283 in patients with imatinib- and second-generation ABL TKI-resistant BCR-ABL(+) cells, including T315I.

The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias

An update on the underlying pathophysiologies of disease progression and IM resistance, and the development of new targeted TK inhibitors for managing CML are provided and the importance of future strategies targeting CML stem cells is discussed.

NS-187 (INNO-406), a Bcr-Abl/Lyn Dual Tyrosine Kinase Inhibitor

NS-187 (INNO-406), a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects is developed, which is a novel drug whose affinity for Abl is higher than that of imatinib and whose specificity in inhibiting Lyn is higherthan that of SFK/Abl inhibitors such as dasatinib (Sprycel™) or bosutinib (SKI-606).

INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity.

It is found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein, and findings indicate that INno-406 is a promising agent for the treatment of CNS Ph+ leukemia.

CT-721, a Potent Bcr-Abl Inhibitor, Exhibits Excellent In Vitro and In Vivo Efficacy in the Treatment of Chronic Myeloid Leukemia

Taken together, CT-721 is a potent and time-dependent Bcr-Abl kinase inhibitor, and has shown strong in vitro and in vivo anti-CML activities with a favorable pharmacokinetic profile, differentiating it from other BCr-A Bl kinase inhibitors already approved and current in development for the treatment of CML.

Nilotinib: a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of leukemias

Nilotinib (Tasigna®) is a novel potent selective oral kinase inhibitor that effectively overcomes imatinib resistance, and has induced high rates of hematologic and cytogenetic responses in CML postImatinib failure.

New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check

Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T315I inhibitor remains a high priority.
...

References

SHOWING 1-10 OF 46 REFERENCES

In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.

It is reported that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for allImatinib-resistant mutants tested, with the exception of T315I.

Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases.

Compared with other pyrido[2,3-d]pyrimidine analogues studied, PD166326 was the most potent inhibitor of Bcr-Abl-dependent cell growth and PD173955 inhibited kit ligand-dependent c-kit autophosphorylation and had a lesser effect on interleukin 3-dependent or granulocyte macrophage colony-stimulating factor-induced cell growth.

Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor

BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinIB-resistant BCR-ABL mutants and illustrates how molecular insight into kinase inhibitors resistance can guide the design of second-generation targeted therapies.

A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance.

  • K. GumireddyS. Baker E. Reddy
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
Kinetic studies demonstrate that this compound is not ATP-competitive but is substrate-competitive and works synergistically with imatinib in wild-type BCR-ABL inhibition, and ON012380 was found to induce apoptosis of all of the known imatin ib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection.

Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML.

The low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate-resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P.

BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571.

Comparison of samples from patients taken prior to and following STI571 failure suggested that expression and/or activation of LYN/HCK occurs during disease progression, and results suggest that acquired STi571 resistance may be associated with BCR-ABL independence and mediated in part through overexpression of other tyrosine kinases.

Mechanisms and implications of imatinib resistance mutations in BCR-ABL

The most common mechanism of relapse for CML patients treated with Imatinib is the appearance of point mutations in the BCR-ABL oncogene that confer resistance to this drug, which mitigates the prospect of a cure for this leukemia.

SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice.

4-anilino-3-quinolinecarbonitrile (SKI-606) ablates tyrosine phosphorylation of Bcr-Abl in CML cells and of v-A Bl expressed in fibroblasts, which causes complete regression of large K562 xenografts in nude mice.

Towards combination target-directed chemotherapy for chronic myeloid leukemia: role of farnesyl transferase inhibitors.

  • G. Daley
  • Biology, Chemistry
    Seminars in hematology
  • 2003
Initial clinical trials in patients with refractory acute myeloid leukemia and CML in blast crisis have shown significant activity, suggesting that trials combining imatinib and FTIs are warranted.