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A novel drug discovery strategy: mechanistic investigation of an enantiomeric antitumor agent targeting dual p53 and NF-?B pathways.

ABSTRACT: The p53 and nuclear factor ?B (NF-?B) 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-?B 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.

SUBMITTER: Zhuang C

PROVIDER: S-EPMC4279413 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Zhuang Chunlin C Sheng Chunquan C Shin Woo Shik WS Wu Yuelin Y Li Jin J Yao Jianzhong J Dong Guoqiang G Zhang Wen W Sham Yuk Yin YY Miao Zhenyuan Z Zhang Wannian W

Oncotarget 20141101 21

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 obse ...[more]

PMID: 25350970

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