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

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.

• Publication year

  2025

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2025-08-18

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.jmedchem.4c02057PMID 40824889
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Loss of p53 epigenetically modulates epithelial to mesenchymal transition in colorectal cancer

  2024cited by this paper
• Translating p53-based therapies for cancer into the clinic

  2024cited by this paper
• Delivery to, and Reactivation of, the p53 Pathway in Cancer Cells Using a Grafted Cyclotide Conjugated with a Cell-Penetrating Peptide.

  2024cited by this paper
• MDM2/MDMX inhibition by Sulanemadlin synergizes with anti-Programmed Death 1 immunotherapy in wild-type p53 tumors

  2024cited by this paper
• Synthesis and applications of mirror-image proteins

  2023cited by this paper
• Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized α-Helical Peptide in Clinical Development.

  2023cited by this paper
• Drugging p53 in cancer: one protein, many targets

  2022cited by this paper
• Turing milk into pro-apoptotic oral nanotherapeutic: De novo bionic chiral-peptide supramolecule for cancer targeted and immunological therapy

  2022cited by this paper
• Turning chiral peptides into a racemic supraparticle to induce the self-degradation of MDM2

  2022cited by this paper
• A nano-predator of pathological MDMX construct by clearable supramolecular gold(I)-thiol-peptide complexes achieves safe and potent anti-tumor activity

  2021cited by this paper
• De Novo Nano-Erythrocyte Structurally Braced by Biomimetic Au(I)-peptide Skeleton for MDM2/MDMX Predation toward Augmented Pulmonary Adenocarcinoma Immunotherapy.

  2021cited by this paper
• The roles and regulation of MDM2 and MDMX: it is not just about p53

  2021cited by this paper
• Design of ultrahigh-affinity and dual-specificity peptide antagonists of MDM2 and MDMX for P53 activation and tumor suppression

  2021cited by this paper
• Peptoid-based reprogrammable template for cell-permeable inhibitors of protein–protein interactions

  2021cited by this paper
• Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type TP53

  2021cited by this paper
• Macrocyclization of an all-d linear α-helical peptide imparts cellular permeability† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c9sc06383h

  2020cited by this paper
• Chiral Protein Supraparticles for Tumor Suppression and Synergistic Immunotherapy - an enabling strategy for bioactive supramolecular chirality construction.

  2020cited by this paper
• Resurrecting a p53 peptide activator - An enabling nanoengineering strategy for peptide therapeutics.

  2020cited by this paper
• Life and Death Decision-Making by p53 and Implications for Cancer Immunotherapy.

  2020cited by this paper
• Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials

  2020cited by this paper
• Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein-Protein Interactions.

  2020cited by this paper
• α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53–MDM2/MDMX Protein–Protein Interactions

  2020cited by this paper
• A general-purpose Nanohybrid fabricated by Polymeric Au(I)-peptide precursor to wake the function of Peptide Therapeutics

  2020cited by this paper
• A tetrameric protein scaffold as a nano-carrier of antitumor peptides for cancer therapy.

  2019cited by this paper
• A lanthanide-peptide-derived bacterium-like nanotheranostic with high tumor-targeting, -imaging and -killing properties.

  2019cited by this paper
• Biomimetic Nanotechnology toward Personalized Vaccines

  2019cited by this paper
• Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles

  2019cited by this paper
• Self-Assembled Peptide-Lanthanide Nanoclusters for Safe Tumor Therapy: Overcoming and Utilizing Biological Barriers to Peptide Drug Delivery.

  2018cited by this paper
• Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers

  2018cited by this paper
• Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy.

  2018cited by this paper
• Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

  2018cited by this paper
• Turning a Luffa Protein into a Self-Assembled Biodegradable Nanoplatform for Multitargeted Cancer Therapy.

  2018cited by this paper
• Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design

  2018cited by this paper
• Cyclotides as drug design scaffolds.

  2017cited by this paper
• Molecular engineering solutions for therapeutic peptide delivery.

  2017cited by this paper
• Local Activation of p53 in the Tumor Microenvironment Overcomes Immune Suppression and Enhances Antitumor Immunity.

  2017cited by this paper
• A comprehensive map of molecular drug targets

  2016cited by this paper
• Small molecules, big targets: drug discovery faces the protein–protein interaction challenge

  2016cited by this paper
• Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status.

  2016cited by this paper
• Emerging roles of p53 and other tumour-suppressor genes in immune regulation

  2016cited by this paper
• Peptide therapeutics: current status and future directions.

  2015cited by this paper
• Toxins and derivatives in molecular pharmaceutics: Drug delivery and targeted therapy.

  2015cited by this paper
• A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.

  2015cited by this paper
• PDL1 Regulation by p53 via miR-34

  2015cited by this paper
• Mirror image proteins.

  2014cited by this paper
• MDM2, MDMX and p53 in oncogenesis and cancer therapy

  2013cited by this paper
• Stapled peptides with improved potency and specificity that activate p53.

  2013cited by this paper
• Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy

  2013cited by this paper
• Human papillomavirus 18 E6 inhibits phosphorylation of p53 expressed in HeLa cells

  2012cited by this paper
• An ultrahigh affinity d-peptide antagonist Of MDM2.

  2012cited by this paper
• Structure of the stapled p53 peptide bound to Mdm2.

  2012cited by this paper
• Targeted delivery of a novel palmitylated D-peptide for antiglioblastoma molecular therapy

  2012cited by this paper
• Designer nanomaterials using chiral self-assembling peptide systems and their emerging benefit for society.

  2012cited by this paper
• Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability

  2011cited by this paper
• Limitations of Peptide Retro-inverso Isomerization in Molecular Mimicry*

  2010cited by this paper
• A left-handed solution to peptide inhibition of the p53-MDM2 interaction.

  2010cited by this paper
• A stapled p53 helix overcomes HDMX-mediated suppression of p53.

  2010cited by this paper
• D-peptide inhibitors of the p53–MDM2 interaction for targeted molecular therapy of malignant neoplasms

  2010cited by this paper
• Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions.

  2010cited by this paper
• Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability.

  2010cited by this paper
• Apamin as a template for structure-based rational design of potent peptide activators of p53.

  2009cited by this paper
• Awakening guardian angels: drugging the p53 pathway

  2009cited by this paper
• Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX

  2009cited by this paper
• In situ neutralization in Boc-chemistry solid phase peptide synthesis. Rapid, high yield assembly of difficult sequences.

  2009cited by this paper
• Turning a scorpion toxin into an antitumor miniprotein.

  2008cited by this paper
• Reaching for high-hanging fruit in drug discovery at protein–protein interfaces

  2007cited by this paper
• Reactivation of the p53 Tumor Suppressor Pathway by a Stapled p53 Peptide

  2007cited by this paper
• Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide.

  2007cited by this paper
• MDMX: from bench to bedside

  2007cited by this paper
• In Situ Neutralization in Boc-chemistry Solid Phase Peptide Synthesis

  2007cited by this paper
• Efficient p53 activation and apoptosis by simultaneous disruption of binding to MDM2 and MDMX.

  2007cited by this paper
• Miniature Protein Inhibitors of the p53–hDM2 Interaction

  2006cited by this paper
• Efficient synthesis of a beta-peptide combinatorial library with microwave irradiation.

  2005cited by this paper
• Coot: model-building tools for molecular graphics.

  2004cited by this paper
• Helical β-Peptide Inhibitors of the p53-hDM2 Interaction

  2004cited by this paper
• Small-molecule inhibitors of protein–protein interactions: progressing towards the dream

  2004cited by this paper
• An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides

  2000cited by this paper
• Surfing the p53 network

  2000cited by this paper
• Mdm2 promotes the rapid degradation of p53

  1997cited by this paper
• Additivity Principles in Biochemistry*

  1997cited by this paper
• Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53

  1997cited by this paper
• Refinement of macromolecular structures by the maximum-likelihood method.

  1997cited by this paper
• [20] Processing of X-ray diffraction data collected in oscillation mode.

  1997cited by this paper
• Identification of d-Peptide Ligands Through Mirror-Image Phage Display

  1996cited by this paper
• How to measure and predict the molar absorption coefficient of a protein

  1995cited by this paper
• Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression

  1995cited by this paper
• The CCP4 suite: programs for protein crystallography.

  1994cited by this paper
• Synthesis of proteins by native chemical ligation.

  1994cited by this paper
• The p53-mdm-2 autoregulatory feedback loop.

  1993cited by this paper
• WAF1, a potential mediator of p53 tumor suppression.

  1993cited by this paper
• p21 is a universal inhibitor of cyclin kinases

  1993cited by this paper
• The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.

  1993cited by this paper
• mdm2 expression is induced by wild type p53 activity.

  1993cited by this paper
• Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53

  1993cited by this paper
• The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.

  1992cited by this paper
• Additivity of mutational effects in proteins.

  1990cited by this paper

• Advances in immunotherapy for thyroid malignancies: from molecular targets to clinical outcomes.

  2026cites this paper