文献类型：期刊文献

英文题名：Discovery and Rational Design of Pteridin-7(8H)-one-Based Inhibitors Targeting FMS-like Tyrosine Kinase 3 (FLT3) and Its Mutants

作者：Sun, Deheng[1];Yang, Yu[1];Lyu, Jiankun[1];Zhou, Wei[1];Song, Wenlin[1];Zhao, Zhenjiang[1];Chen, Zhuo[1];Xu, Yufang[1];Li, Honglin[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2016

卷号：59

期号：13

起止页码：6187

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000379989800016)】；

基金：The research was supported in part by the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (Grants 21302054, 81222046, 21173076, and 81230076) (Z.C., H.L.), the Shanghai Committee of Science and Technology (Grants 14431902100 and 13ZR1453100) (Y.X, Z.C.), the National S&T Major Project of China (Grant 2013ZX09507004), the Twelfth Five-Year National Science & Technology Support Program (Grant 2012BAI29B06), and the 863 Hi-Tech Program of China (Grant 2012AA020308) (H.L.). H.L. is also sponsored by Specialized Research Fund for the Doctoral Program of Higher Education (Grant 20130074110004), the Innovation Program of Shanghai Municipal Education Commission (Grant 13SG32), and Fok Ying Tung Education Foundation (Grant 141035).

语种：英文

摘要：FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7(8H)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (31) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar K-D for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7(8H)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G(0)/G(1) cell cycle arrest and apoptosis in AML cells. In in vivo studies, 31 significantly suppresses the tumor growth in MV4-11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for AML treatment.