Treatment of Acute Myeloid Leukemia (AML) with the Multi-kinase FLT3-IRAK1/4 Inhibitor, NCGC1481, to Avoid Adaptive Resistance

Description:

This technology includes the identification and use of a novel small molecule, NCGC1481, to inhibit both the FLT3 and IRAK1/4 kinase pathways for treating acute myeloid leukemia (AML). An activating mutation of the FMS-like receptor kinase 3 (FMT3) occurs in approximately 25% of AML cases. Consequently, FLT3 inhibitors (FLT3i) have a good initial clinical response, however patients relapse with FLT3i-resistance. This adaptive resistance following FLT3i treatment is partially conferred by activation of the IRAK1/4 kinase complex. Given the challenges of achieving multi-drug combination regimens, a high-throughput screen was performed to identify compounds that could inhibit both FLT3i and IRAK1/4 kinases simultaneously. The multi-kinase FLT3-IRAK1/4 inhibitor NCGC1481eliminated adaptive resistant FLT3-ITD AML cells in vitro and in vivo, and displayed superior efficacy as compared to current targeted FLT3 therapies.