2. Academic Validation
  3. A Dual-Specificity d-Peptide Antagonist of MDM2 and MDMX for Antitumor Immunotherapy

A Dual-Specificity d-Peptide Antagonist of MDM2 and MDMX for Antitumor Immunotherapy

  • J Med Chem. 2025 Aug 28;68(16):16940-16957. doi: 10.1021/acs.jmedchem.4c02057.
Chongbing Liao 1 2 3,  Jin Yan 4,  William D Tolbert 5,  Xishan Chen 6,  Marzena Pazgier 5,  Weiyue Lu 6,  Changyou Zhan 1 3,  Wuyuan Lu 2
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 3 State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200438, China.
  • 4 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
  • 5 Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, United States.
  • 6 Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China.
PMID: 40824889 DOI: 10.1021/acs.jmedchem.4c02057
Abstract

Designing metabolically stable peptides to target interactions of the tumor suppressor protein p53 with the two oncogenic proteins MDM2 and MDMX represents an attractive approach to harvesting "high-hanging fruits" often inaccessible to traditional Anticancer drug discovery and development efforts. Here, we report the design of a proteolysis-resistant d-dodecapeptide, termed DPMI-ω (EFWYVEp-ClFEKLLR), capable of disrupting the p53-MDM2/MDMX complex by antagonizing MDM2 and MDMX. DPMI-ω, upon fabrication on gold nanoparticles, efficiently traversed tumor cells and killed them by reactivating the p53 signaling pathway. Further, DPMI-ω inhibited B16 melanoma growth in vivo and, when combined with an anti-PD1 antibody, powerfully augmented the efficacy of immunotherapy by expanding CD3+/CD8+ cytotoxic T cells and suppressing CD4+/CD25+ regulatory T cells. Our work validates the design of a therapeutically viable Anticancer peptide, showcasing its potential in combination therapy to treat patients with tumors that are otherwise resistant or poorly responsive to antitumor immunotherapy.

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