Small Molecules Simultaneously Inhibiting p53-Murine Double Minute 2 (MDM2) Interaction and Histone Deacetylases (HDACs): Discovery of Novel Multitargeting Antitumor Agents

Shipeng He, Guoqiang Dong, Shanchao Wu, Kun Fang, Zhenyuan Miao, Wei Wang, Chunquan Sheng

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

p53-Murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs) are important targets in antitumor drug development. Inspired by the synergistic effects between MDM2 and HDACs, the first MDM2/HDACs dual inhibitors were identified, which showed excellent activities against both targets. In particular, compound 14d was proven to be a potent and orally active MDM2/HDAC dual inhibitor, whose antitumor mechanisms were validated in cancer cells. Compound 14d showed excellent in vivo antitumor potency in the A549 xenograft model, providing a promising lead compound for the development of novel antitumor agents. Also, this proof-of-concept study offers a novel and efficient strategy for multitargeting antitumor drug discovery.

Original languageEnglish (US)
Pages (from-to)7245-7260
Number of pages16
JournalJournal of Medicinal Chemistry
Volume61
Issue number16
DOIs
StatePublished - Aug 23 2018
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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