Discovery of a Potent FLT3 Inhibitor (E)-4-(3-(3-Fluoro-4-(morpholinomethyl)styryl)-1H-indazol-6-yl)pyridin-2-amine for the Treatment of Acute Myeloid Leukemia with Multiple FLT3 Mutations.

Abstract

Targeting FLT3 genetic alterations has emerged as a promising therapeutic approach for AML. However, the rapid emergence of resistance to FLT3 inhibitors has severely curtailed their clinical utility. Herein, we developed a series of (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyridin-2-amine derivatives to overcome FLT3 resistance mutations. Among them, 10q exhibited potent and selective inhibitory activities against FLT3-ITD-positive AML cells and inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis. It also possessed excellent potencies against BaF3 cells harboring FLT3 mutations conferring resistance to FLT3 inhibitors, as well as quizartinib-resistant MV4-11 cells (MV4-11/AC220R). Moreover, 10q demonstrated an oral bioavailability of 11.01% and potent antitumor potency in an MV4-11 xenograft model without obvious toxicity. Furthermore, 10q could effectively suppress tumor growth in both MV4-11/AC220R and BaF3-FLT3-ITD-D835I mouse models. 10q thus might be an efficient and potent FLT3 inhibitor with the capacity for overcoming multiple FLT3 mutations.