This technology includes a series of imidazo[1,2-a]pyrazines that display potent inhibition of FLT3, as well as potent binding and activity against FLT3 tyrosine kinase domain and gatekeeper mutations. This chemotype exhibits superior anti-leukemic activity against the common clinically-relevant FLT3-mutant acute myeloid leukemia (AML) in vitro and in vivo. Tyrosine kinase domain mutations are a common cause of acquired resistance to FLT3 inhibitors used to treat FLT3-mutant AML.
If successful in human clinical trials, these agents could be used to treat a variety of hematological diseases, including but not limited to AML, myelodysplastic syndrome, diffuse large B-cell lymphoma, and other blood cancers.
These agents have activity versus mutations in the acquired resistance space and versus non-IRAK inhibitors in the adaptive resistance space.