2. Academic Validation
  3. Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment

Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment

  • Cancer Cell. 2016 Oct 10;30(4):623-636. doi: 10.1016/j.ccell.2016.08.015.
Lubing Gu 1,  Hailong Zhang 1,  Tao Liu 1,  Sheng Zhou 2,  Yuhong Du 3,  Jing Xiong 2,  Sha Yi 1,  Cheng-Kui Qu 1,  Haian Fu 3,  Muxiang Zhou 4
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA 30322, USA.
  • 2 Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 3 Department of Pharmacology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 4 Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA 30322, USA. Electronic address: [email protected].
PMID: 27666947 DOI: 10.1016/j.ccell.2016.08.015
Abstract

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.

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