Novel Compounds to treat AML, MDS
Cincinnati Children’s has developed novel small molecule inhibitors that target both IRAK1/4 and mutant FLT3, thereby eradicating leukemic cells. In vitro data has shown that the inhibitor alone is effective at inhibiting both pathways, eradicating leukemic cells, and preventing future growth. In a FLT3-mutant AML xenograft mouse model, the novel compounds extended median survival. Further, the novel compounds inhibited MDS-propagating cells at sub-micromolar doses, which are more potent than commercially available IRAK 1/4 inhibitors.
AML has activating mutations in the FLT3 receptor and compensatory activation of IRAK1/4, an IL1 receptor kinase complex, upon inhibition of FLT3. Current treatments are limited by their ability to only inhibit FLT3 mutations, allowing for new cancer growth due in part to IRAK1/4 activation. While in MDS, IRAK1/4 is persistently in an active state.