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.