G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia

Abstract

Key Points A novel inhibitor G-749 is very potent against FLT3 kinase mutants including D835Y and ITD/F691L that confer resistance to PKC412 and AC220. G-749 shows several desirable characteristics to overcome other drug resistances conferred by patient plasma, FLT3 ligand, and stromal cells.

FLT3 Inhibitors for Treating Acute Myeloid Leukemia

“…Several agents (AMG 925, SAR302503, Ponatinib, G-749..) might overcome FLT3 Inhibitor resistance as shown in some preclinical studies (55)(56)(57)(58).…”

Emerging strategies for high-risk and relapsed/refractory acute myeloid leukemia: Novel agents and approaches currently in clinical trials

“…Another potential advantage of crenolanib is its reduced inhibition of c-Kit compared with quizartinib. G-749 is a novel FLT3 inhibitor that has potent and sustained in vitro inhibition of the FLT3 wild type and FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L [30]. It has antileukemia activity in human AML bone marrow blasts regardless of FLT3 mutation and shows activity in animal models.…”

HMGA2 as a potential molecular target inKMT2A-AFF1-positive infant acute lymphoblastic leukaemia

“…Therefore, new treatment strategies, such as molecular targeting therapy, are needed. To date, several target molecules have been identified, such as DOT1L, FLT3, and menin, but clinical usefulness of their inhibitors in the treatment of KMT2A-rearranged leukaemia is still under investigation (Wang et al, 2008;Dawson et al, 2011;Grembecka et al, 2012;Daigle et al, 2013;Cao et al, 2014;Lee et al, 2014a;Xu et al, 2015). The identification of alternative molecules is necessary to improve the outcome and quality of patients' lives.…”