Luxeptinib (CG-806) simultaneously targets FLT3 and select other kinase pathways operative in myeloid malignancies. We investigated the range of kinases it inhibits, its cytotoxicity landscape ex vivo with acute myeloid leukemia (AML) patient samples, and its efficacy in xenograft models. Luxeptinib inhibits wild type and many of the clinically relevant mutant forms of FLT3 at low nanomolar concentrations. It is a more potent inhibitor of the activity of FLT3-ITD, FLT3 kinase domain and gatekeeper mutants than against wild type FLT3. Broad kinase screens disclosed that it also inhibits other kinases that can drive oncogenic signaling and rescue pathways, but spares kinases known to be associated with clinical toxicity. In vitro profiling of luxeptinib against 186 AML fresh patient samples demonstrated greater potency relative to other FLT3 inhibitors, including cases with mutations in FLT3, IDH1/2, ASXL1, NPM1, SRSF2, TP53 or RAS, and activity was documented in a xenograft AML model. Luxeptinib administered continuously PO every 12 h at a dose that yielded a mean Cmin plasma concentration of 1.0 {plus minus} 0.3 µM (SEM) demonstrated strong antitumor activity but no myelosuppression or evidence of tissue damage in mice or dogs in acute toxicology studies. On the basis of these studies, luxeptinib was advanced into a phase 1 trial for patients with AML and myelodysplastic/myeloproliferative neoplasms (MDS/MPN).

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