The adenosine triphosphate (ATP)-- competitive kinase
inhibitors imatinib (STI571; trade name: Gleevec), dasatinib, and nilotinib inhibit multiple tyrosine kinases in addition to ABL1 and ABL2 (5).
This work, and that of colleagues Brian Druker and Novartis, led to the development of the kinase
inhibitor imatinib (Gleevec) as primary therapy for chronic myelogenous leukemia (CML), and the discovery that imatinib resistance is caused by BCR - ABL kinase domain mutations.
Not exact matches
The allosteric
inhibitor GNF - 5, however, stabilizes the closed, inactivated state, and even recloses the
imatinib - induced open state.
In the late 1990s, STI - 571 (
imatinib, Gleevec / Glivec) was identified by the pharmaceutical company Novartis (then known as Ciba Geigy) in high - throughput screens for tyrosine kinase
inhibitors.
The use of alternative KIT
inhibitors following progression on
imatinib has achieved clinical benefit in patients with advanced GIST.
Several phase 1 and 2 trials have been carried out using nonselective ATP - competitive
inhibitors such as
imatinib to treat patients with advanced breast cancer.
These mutant kinases are attractive therapeutic targets, as demonstrated by the efficacy of
imatinib in BCR - ABL — positive chronic myelogenous leukemia (CML), 5 as well as in MPD associated with activating alleles involving PDGFRA or PDGFRB.2, 6,7 In addition, activating mutations in the FLT3 receptor tyrosine kinase are the most common genetic event in acute myeloid leukemia (AML), and specific
inhibitors of the FMS - like tyrosine kinase 3 (FLT3) have entered late - stage clinical trials.8 Although mutations in tyrosine kinases and in other genes have been identified in a subset of MPD and AML, in many cases the genetic events that contribute to the molecular pathogenesis of these diseases remain unknown.