Discovery of Novel p53-MDM2 Inhibitor (RG7388)-Conjugated PlatinumIV Complexes as Potent Antitumor Agents

  • J Med Chem. 2024 Jun 13;67(11):9645-9661. doi: 10.1021/acs.jmedchem.4c00784.
Wei Liu  1  2 ,  Yi Ma  2 ,  Youyou He  2 ,  Yanhong Liu  2 ,  Zhongjie Guo  1 ,  Jin He  1 ,  Xiaodong Han  1 ,  Yujiao Hu  1 ,  Muqiong Li  1 ,  Ru Jiang  1 ,  Shengzheng Wang  1
Affiliations
  • 1. Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 2. Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi 710021, China.
PMID: 38776419 DOI: 10.1021/acs.jmedchem.4c00784
Abstract

While a number of p53-MDM2 inhibitors have progressed into clinical trials for the treatment of Cancer, their progression has been hampered by a variety of problems, including acquired drug resistance, dose-dependent toxicity, and limited clinical efficiency. To make more progress, we integrated the advantages of MDM2 inhibitors and platinum drugs to construct novel PtIV-RG7388 (a selective MDM2 Inhibitor) complexes. Most complexes, especially 5a and 5b, displayed greatly improved antiproliferative activity against both wild-type and mutated p53 Cancer cells. Remarkably, 5a exhibited potent in vivo tumor growth inhibition in the A549 xenograft model (66.5%) without apparent toxicity. It arrested the cell cycle at both the S phase and the G2/M phase and efficiently induced Apoptosis via the synergistic effects of RG7388 and cisplatin. Altogether, PtIV-RG7388 complex 5a exhibited excellent in vitro and in vivo antitumor activities, highlighting the therapeutic potential of PtIV-RG7388 complexes as antitumor agents.

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