Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment.
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.
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.
Lubing
L
Gu
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.
Hailong
H
Zhang
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.
Tao
T
Liu
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Sheng
S
Zhou
Department of Pharmacology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Yuhong
Y
Du
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Jing
J
Xiong
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.
Sha
S
Yi
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.
Cheng-Kui
CK
Qu
Department of Pharmacology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Haian
H
Fu
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: mzhou@emory.edu.
Muxiang
M
Zhou
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
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