- Discovery of the novel potent and selective FLT3 inhibitor 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl} -3-p-tolylurea and its anti-acute myeloid leukemia (AML) activities in vitro and in vivo
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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, 3,4]thiadiazol-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.
- Li, Wei-Wei,Wang, Xiao-Yan,Zheng, Ren-Lin,Yan, Heng-Xiu,Cao, Zhi-Xing,Zhong, Lei,Wang, Ze-Rong,Ji, Pan,Yang, Ling-Ling,Wang, Li-Jiao,Xu, Yong,Liu, Jing-Jing,Yang, Jiao,Zhang, Chun-Hui,Ma, Shuang,Feng, Shan,Sun, Qi-Zheng,Wei, Yu-Quan,Yang, Sheng-Yong
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p. 3852 - 3866
(2012/07/14)
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