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Author Notes:

Correspondence: mzhou@emory.edu

Lubing Gu, Hailong Zhang, Tao Liu, and Sheng Zhou are co-first authors of this work.

M.Z. conceived the project, designed the experiments and wrote the manuscript; L.G., H.Z., T.L. and S.Z. designed and performed most of the experiments including FP-HTS, binding and ubiquitination assays, polysome profiling, pathology and animal studies; J.X. and S.Y. performed cell culture, Western blot, WST cytotoxic analysis and flow cytometry studies.

Y.D., C.Q. and H.F provided technique support and chemical libraries for FP-HTS.

We thank J. Yang (Georgia State University) for fluorescent titration support, K.Y. Chiang (Emory University) for providing human NBMM cells, and H. Findley (Emory University) for editing the manuscript.

Subjects:

Research Funding:

This work was supported by R01 grants (CA180519, CA123490 and CA143107) to M.Z.; the Scholar award (79387GA) from Hyundai Hope on Wheels to M.Z.; research grants from CURE Childhood Cancer to M.Z and L.G; U01 grant (CA168449) to H.F.; and a National Natural Science Foundation of China grant (No.81472488) to S.Z.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • ACUTE LYMPHOBLASTIC-LEUKEMIA
  • MESSENGER-RNA STABILIZATION
  • SMALL-MOLECULE INHIBITORS
  • WILD-TYPE P53
  • PROTEIN OVEREXPRESSION
  • APOPTOSIS PROTEINS
  • GENE AMPLIFICATION
  • CELLS
  • ACTIVATION
  • PATHWAY

Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment

Tools:

Journal Title:

Cancer Cell

Volume:

Volume 30, Number 4

Publisher:

, Pages 623-636

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2016 Elsevier Inc.

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