Design, synthesis and biological evaluation of indolin-2-one-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase3 (FLT3)

被引:21
作者
Ma, Fei [1 ]
Liu, Peng [1 ]
Lei, Min [1 ]
Liu, Jian [2 ]
Wang, Hongtao [3 ]
Zhao, Shaohua [3 ]
Hu, Lihong [1 ,2 ]
机构
[1] East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China
[2] Nanjing Univ Chinese Med, Sch Pharm, 138 Xianlin Rd, Nanjing 200237, Jiangsu, Peoples R China
[3] Shijiazhuang Yiling Pharmceut Co, 238 Tianshan St, Shijiazhuang 050035, Peoples R China
基金
中国国家自然科学基金;
关键词
Indolin-2-one derivatives; FLT3; inhibitors; Structure -activity relationships (SARs); Acute myeloid leukemia (AML); In vivo study; ACUTE MYELOID-LEUKEMIA; IN-VIVO; ACTIVATING MUTATION; RESISTANCE; SORAFENIB; RECEPTOR; THERAPY; SU11248; PKC412; DOMAIN;
D O I
10.1016/j.ejmech.2016.12.038
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of acute myeloid leukemia (AML) patients, which has been proposed as a promising drug target for AML therapy. A series of indolin-2-one derivatives bearing different groups at the solvent interface position based on sunitinib as FLT3 inhibitors were designed, synthesized and evaluated in FLT3-dependent human AML cell line MV4-11. Structure-activity relationship (SAR)analysis showed that heterocyclic alkane at the solvent interface position could significantly increase the potency for the inhibition of proliferation of MV4-11 cell line. Compound 10a and 10d exhibited better efficacy (MV4-11, IC50: 14.7 nM for 10a and 24.8 nM for 10d) than positive control sunitinib (MV4-11, IC50: 38.5 nM). The kinase and cellular inhibition assay exhibited that 10d (FLT3, IC50: 5.3 nM) was a potent and selective FLT3 inhibitor. Furthermore, the pharmacokinetic experiments showed that 10d had good properties of oral bioavailability, C-max, T-max, T-1/2 and AUC in mice, respectively. The in vivo study indicated that 10d could significantly suppress tumor growth in MV4-11 xenografts nude mice model and occupied with a commendable therapeutic window compared to sunitinib. (C) 2016 Published by Elsevier Masson SAS.
引用
收藏
页码:72 / 86
页数:15
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