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

Abstract

Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph þ ) 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 þ 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 (IC50o30 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 þ 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 imatinibrefractory and late-stage disease are discussed.

BCR-ABLalternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations

“…As reported by von Bubnoff et al (37), the position change of E286 due to T315I may be the reason for nilotinib resistance. Although dasatinib does not seem to interact directly with E286, T315I still causes dasatinib resistance (36). Our finding is also consistent with the suggestion of Levison et al (22) that resistance to dasatinib is most likely due to the effects of T315I on the whole C-helix, which prevents formation of an active Src site.…”

“…Weisberg et al (36) showed that, like imatinib, nilotinib has close contact with E286. As reported by von Bubnoff et al (37), the position change of E286 due to T315I may be the reason for nilotinib resistance.…”

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

“…Nilotinib inhibits most imatinib-resistant BCR-ABL forms, except T315I, in vitro at concentrations approved for and tested in patients. 17 Nilotinib is 30-fold more potent than imatinib at inhibiting BCR-ABL (Table 2). 18,19 Early data on nilotinib in newly diagnosed CML patients suggest clinical activity with the potential to exceed first-line imatinib efficacy, pending longer follow-up data.…”

Experimental treatment of human diffuse large B‐cell lymphoma xenografts by doxycycline alone or in combination with the anti‐CD20 chimeric monoclonal antibody rituximab

“…F359 mutations that are associated with amino acid substitutions in the catalytic region include (Phe359Ala) F359A, Phe359Val (F359V), Phe359Ile (F359I), or Phe359Cys (F359C) as detected in this patient. Like imatinib mesylate, nilotinib binds to the inactive Abl kinase conformation, with the P-loop folding over the ATP-binding site, and the activation-loop blocking the substrate binding site, to disrupt the ATPphosphate-binding site and inhibit the catalytic activity of the enzyme [13]. Dasatinib was originally developed as a Src kinase inhibitor and is structurally distinct from imatinib.…”