Discovery of the Novel Potent and Selective FLT3 Inhibitor 1-5-7- (3- Morpholinopropoxy) quinazolin-4-ylthio-1, 3, 4thiadiazol-2-yl-3-p-tolylurea and Its Anti-Acute Myeloid Leukemia (AML) Activities in Vitro and in Vivo

Structure-activity relationship (SAR) studies of 2- (quinazolin-4-ylthio) thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2- (6, 7-dimethoxyquinazolin-4-ylthio) thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-5-7- (3-morpholinopropoxy) quinazolin-4-ylthio-1, 3, 4thiadiazol-2-yl-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.