Acute myeloid leukemia (AML) is the second most common leukemia in the U.S., with an estimated 13,000 new cases and 9,000 deaths in 2011.  Approximately 25-30% of AML patients harbor an internal tandem duplication (ITD) mutation in the FLT3 receptor tyrosine kinase, and this mutation constitutively activates FLT3 and correlates with a poor disease outcome.  Inhibitors of ITD-mutated FLT3 may therefore be useful in the treatment of AML.  Our starting point, compound 1 , had a > 100-fold selectivity for FLT3 [IC50 = 23 nM, fluorescence polarization (FP)] over the closely related c-fms and PDGFR� kinases (IC50 > 3 uM; FP).  Optimization of four regions of the molecule focused on improving the rodent PK and the cell-based potency in the presence of plasma.  This effort culminated in the discovery of compound 2 , a dual FLT3/cKit inhibitor (IC50 = 3 nM/40 nM; FP) that prevents ITD-mutated FLT3-driven cell proliferation in the absence (IC50 = 38 nM) and presence of 50% plasma (IC50 = 148 nM), and maintains ~100- >1000-fold selectivity over ~70 kinases tested (c-fms IC50 = 3.8 uM, PDGFR� IC50 > 20 uM; FP).  In an MV4-11 ITD-FLT3-driven mouse xenograft model, compound 2  at 30 and 100 mpk b.i.d. regresses tumor weight by 85% and 99%, respectively.    The design, synthesis, and in vitro and in vivo SAR of this novel series will be presented.

Orally efficacious, selective FLT3 inhibitor for the treatment of acute myeloid leukemia

243rd National Meeting (2012)

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