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.
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.
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.