A novel drug discovery strategy: Mechanistic investigation of an enantiomeric antitumor agent targeting dual p53 and NF-κB pathways

Chunlin Zhuang, Chunquan Sheng, Woo Shik Shin, Yuelin Wu, Jin Li, Jianzhong Yao, Guoqiang Dong, Wen Zhang, Yuk Yin Sham, Zhenyuan Miao, Wannian Zhang

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The p53 and nuclear factor κB (NF-κB) pathways play crucial roles in human cancer development. Simultaneous targeting of both pathways is an attractive therapeutic strategy against cancer. In this study, we report an antitumor molecule that bears a pyrrolo[3,4-c]pyrazole scaffold and functions as an enantiomeric inhibitor against both the p53-MDM2 interaction and the NF-κB activation. It is a first-in-class enantiomeric inhibitor with dual efficacy for cancer therapy. Synergistic effect was observed in vitro and in vivo. Docking and molecular dynamics simulation studies further provided insights into the nature of stereoselectivity.

Original languageEnglish (US)
Pages (from-to)10830-10839
Number of pages10
JournalOncotarget
Volume5
Issue number21
DOIs
StatePublished - 2014

Keywords

  • Dual inhibitors
  • Enantiomer
  • Molecular dynamics
  • Molecular recognition
  • Nf-κb
  • P53-MDM2
  • antitumor activity

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    Zhuang, C., Sheng, C., Shin, W. S., Wu, Y., Li, J., Yao, J., Dong, G., Zhang, W., Sham, Y. Y., Miao, Z., & Zhang, W. (2014). A novel drug discovery strategy: Mechanistic investigation of an enantiomeric antitumor agent targeting dual p53 and NF-κB pathways. Oncotarget, 5(21), 10830-10839. https://doi.org/10.18632/oncotarget.2521