Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment

被引：72

作者：

Gu, Lubing ^{[1
]}

Zhang, Hailong ^{[1
]}

Liu, Tao ^{[1
]}

Zhou, Sheng ^{[3
]}

Du, Yuhong ^{[2
]}

Xiong, Jing ^{[3
]}

Yi, Sha ^{[1
]}

Qu, Cheng-Kui ^{[1
]}

Fu, Haian ^{[2
]}

Zhou, Muxiang ^{[1
]}

机构：

[1] Emory Univ, Sch Med, Aflac Canc & Blood Disorders Ctr, Div Hematol Oncol,Dept Pediat, 1760 Haygood Dr, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Pharmacol, Emory Chem Biol Discovery Ctr, Atlanta, GA 30322 USA

[3] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Inst Pathol, Wuhan 430030, Peoples R China

来源：

CANCER CELL | 2016年 / 30卷 / 04期

基金：

中国国家自然科学基金;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; MESSENGER-RNA STABILIZATION; SMALL-MOLECULE INHIBITORS; WILD-TYPE P53; PROTEIN OVEREXPRESSION; APOPTOSIS PROTEINS; GENE AMPLIFICATION; CELLS; ACTIVATION; PATHWAY;

D O I：

10.1016/j.ccell.2016.08.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

MDM2 and XIAP are mutually regulated. Binding of MDM2 RING protein to the IRES region on XIAP mRNA results in MDM2 protein stabilization and enhanced XIAP translation. In this study, we developed a protein-RNA fluorescence polarization (FP) assay for high-throughput screening (HTS) of chemical libraries. Our FP-HTS identified eight inhibitors that blocked the MDM2 protein XIAP RNA interaction, leading to MDM2 degradation. The compound-induced MDM2 downregulation resulted not only in inhibition of XIAP expression, but also in activation of p53, which contributed to cancer cell apoptosis in vitro and inhibition of cancer cell proliferation in vivo. Importantly, one of the MDM2/XIAP inhibitors, MX69, showed minimal inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in animal models.

引用

页码：623 / 636

页数：14

共 42 条

[1] Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells [J].