Identification of a new class of natural product MDM2 inhibitor: In vitro and in vivo anti-breast cancer activities and target validation

Oncotarget
Jiang-Jiang QinRuiwen Zhang

Abstract

The MDM2 oncogene has been suggested as a molecular target for treating human cancers, including breast cancer. Most MDM2 inhibitors under development are targeting the MDM2-p53 binding, and have little or no effects on cancers without functional p53, such as advanced breast cancer. The present study was designed to develop a new class of MDM2 inhibitors that exhibit anticancer activity in MDM2-dependent and p53-independent manners. The selective MDM2 inhibitors were discovered by a computational structure-based screening, yielding a lead compound, termed JapA. We further found that JapA inhibited cell growth, decreased cell proliferation, and induced G2/M phase arrest and apoptosis in breast cancer cells through an MDM2-dependent mechanism, regardless of p53 status. It also inhibited the tumor growth and lung metastasis in breast cancer xenograft models without causing any host toxicity. Furthermore, JapA directly bound to MDM2 protein and reduced MDM2 levels in cancer cells in vitro and in vivo by promoting MDM2 protein degradation and inhibiting MDM2 transcription, which is distinct from the existing MDM2 inhibitors. In conclusion, JapA represents a new class of MDM2 inhibitor that exerts its anticancer activity through dire...Continue Reading

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Citations

Nov 14, 2015·Annual Review of Pharmacology and Toxicology·Daniel Martinez Molina, Pär Nordlund
Feb 2, 2018·Frontiers in Pharmacology·Jiang-Jiang QinRuiwen Zhang
Oct 7, 2019·Medicinal Research Reviews·Wei WangRuiwen Zhang
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May 15, 2021·Journal of Evidence-based Medicine·Dehua YuJiangjiang Qin
Sep 17, 2021·Journal of Cancer Research and Therapeutics·Tahani H AlbinhassanAdel M Al-Ghazzawi

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Methods Mentioned

BETA
xenograft
immunoprecipitation
thermal shift
ubiquitination
Assay
transfection
xenografts

Software Mentioned

OPLS
JapA
Protein Preparation Wizard
Prism
Maestro
Graph Pad
Ligprep

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