PHI-101: a novel FLT3 inhibitor with potent activity against the F691L gatekeeper resistance mutation

Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy characterized by myeloproliferation, a block in differentiation, and accumulation of immature blasts in the bone marrow and peripheral blood [ 1 , 2 ]. The pathogenesis of AML is genetically diverse, with recurrent chromosomal and molecular alterations that drive leukemogenesis and influence prognosis and treatment decisions [ 1 , 2 ]. Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are among the most prevalent in AML and are strongly associated with relapse and reduced survival. Internal tandem duplication (ITD) mutations of the juxtamembrane region are the most common along with point mutations in the tyrosine kinase domain (FLT3-TKD), with both promoting constitutive kinase activity, albeit with distinct downstream effects [ 3 , 4 , 5 , 6 , 7 ]. FLT3 mutations have therefore become important therapeutic targets, leading to the development of small-molecule tyrosine kinase inhibitors (TKIs) [ 8 ].