G-749, a novel FLT3 kinase inhibitor can overcome drug resistance for the treatment of Acute Myeloid Leukemia
Menée à l'aide de modèles murins, cette étude évalue l'activité antitumorale d'un composé appelé G-749, un inhibiteur de FLT3, pour le traitement des patients atteints d'une leucémie myéloïde aiguë récidivante et réfractaire
Aberrant activations of the receptor tyrosine kinase FLT3 are implicated in the pathogenesis of 20–30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased lifespan in animal models. Thus, G-749 appears to be a promising next generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/-TKD mutants and further shows ability to overcome drug resistance.