AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL.

Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
British Journal of Cancer (Impact Factor: 4.82). 06/2006; 94(12):1765-9. DOI: 10.1038/sj.bjc.6603170
Source: PubMed

ABSTRACT Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) are caused by the BCR-ABL oncogene. Imatinib inhibits the tyrosine kinase activity of the BCR-ABL protein and is an effective, frontline therapy for chronic-phase CML. However, accelerated or blast-crisis phase CML patients and Ph+ ALL patients often relapse due to drug resistance resulting from the emergence of imatinib-resistant point mutations within the BCR-ABL tyrosine kinase domain. This has stimulated the development of new kinase inhibitors that are able to over-ride resistance to imatinib. The novel, selective BCR-ABL inhibitor, AMN107, was designed to fit into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. In addition to being more potent than imatinib (IC50< 30 nM) against wild-type BCR-ABL, AMN107 is also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. In preclinical studies, AMN107 demonstrated activity in vitro and in vivo against wild-type and imatinib-resistant BCR-ABL-expressing cells. In phase I/II clinical trials, AMN107 has produced haematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. Dasatinib (BMS-354825), which inhibits Abl and Src family kinases, is another promising new clinical candidate for CML that has shown good efficacy in CML patients. In this review, the early characterisation and development of AMN107 is discussed, as is the current status of AMN107 in clinical trials for imatinib-resistant CML and Ph+ ALL. Future trends investigating prediction of mechanisms of resistance to AMN107, and how and where AMN107 is expected to fit into the overall picture for treatment of early-phase CML and imatinib-refractory and late-stage disease are discussed.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure.
    BioMed Research International 01/2014; 2014:743868. · 2.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer is one of the major health problems with a high mortality rate. Apart from the genetic changes in cancer cells, epigenetic and environmental factors play an important role towards the progression of tumor. The new cancer cases worldwide are estimated to increase to 19.3 million per year by 2025, due to the changing lifestyle and increase in longevity. Social and economic changes have contributed to rising risks of cancers associated with dietary and hormonal factors. Although traditional therapies have been effective in cancer treatment, they often have adverse side effects due to their non specific action on both normal and tumor cells. Therefore, targeted treatment strategies using small molecule inhibitors are being extensively studied. These compounds are usually ≤500Da size and are often administered orally. Their small size also allows them to translocate through the plasma membrane and interact with the cytoplasmic domain of cell-surface receptors and intracellular signaling molecules. In principle, small molecule compounds can be developed to target any portion of a molecule, regardless of the target’s cellular location. In this review, we provide a summary of the small molecule inhibitors (SMIs) used in the cancer therapy, and elaborate on the recent advances in cancer therapies with emphasis on SMIs that block the growth of cancer cells.
    intergrative cancer science and therapeutics. 11/2014; 1(3):39-46.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in two separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single-dose of nilotinib 600 mg, midazolam 4 mg and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single-dose of midazolam 2 mg on Day 1 and 13, and nilotinib 400 mg twice daily from Day 2 to 13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUCinf ) of midazolam plus nilotinib versus midazolam was 1.3 (90% CI, 1.2-1.5) and the maximum observed serum concentration (Cmax ) was 1.2 (90% CI, 1.0-1.4). In the repeated-dose study, the values for AUCinf and Cmax were 2.6 (90% CI, 2.1-3.3) and 2.0 (90% CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Journal of Clinical Pharmacology 11/2014; · 2.47 Impact Factor

Full-text (2 Sources)

Available from
May 28, 2014