Inhibition of FLT3 as a strategy for improving outcome in AML

FLT3 mutations are an independent indicator of a poor prognosis in AML patients under the age of 65 in most studies, and are thus an attractive target for therapeutic intervention. This approach of targeting constitutively activated kinases with selective small-molecule inhibitors has been validated by Druker, Sawyers, Kantarjian and colleagues in demonstrating the efficacy of the ABL kinase inhibitor imatinib (Gleevec) in BCR-ABL-positive chronic myelogenous leukemia.

Similar strategies have been used to identify selective inhibitors of FLT3. We have developed cell-based screens for specific inhibitors of FLT3. Using this approach, in collaboration with Novartis Pharma and Millenium respectively, we have identified several FLT3-selective inhibitors that have suitable properties for use in clinical trials in humans. These include PKC412 from Novartis Pharma and MLN518 (CT53518) from Millenium. Other agents with similar activity include SU11248, SU5614 and SU5416 from SuGen, and CEP-701 developed by Small and colleagues in collaboration with Cephalon. Each of these inhibitors is selective rather than specific. For example, MLN518 is also a potent inhibitor of KIT and platelet-derived growth factor receptor (PDGFR); CEP-701 also inhibits transforming tyrosine kinase protein (TRKA); PKC412 inhibits KIT, PDGFR and protein kinase C; SU11248 also inhibits KIT and PDGFR.

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