2. Academic Validation
  3. Development of Next Generation Cell-Permeable Peptide Inhibitors for the Oncological Target MAGE-A4

Development of Next Generation Cell-Permeable Peptide Inhibitors for the Oncological Target MAGE-A4

  • J Med Chem. 2025 Sep 25;68(18):19377-19395. doi: 10.1021/acs.jmedchem.5c01540.
Jiwoong Lim 1 2,  Lilly F Chiou 3 4,  Brandon Novy 2 5,  Emma J Chow 2 6,  Jacqueline L Norris-Drouin 1 2,  P Brian Hardy 1 2,  Konstantin I Popov 1 2,  Cyrus Vaziri 3 4 7 8,  Albert A Bowers 1 2 6,  Kenneth H Pearce 1 2 7 8
Affiliations

Affiliations

  • 1 Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 5 Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 6 Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 7 Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 8 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 40937506 DOI: 10.1021/acs.jmedchem.5c01540
Abstract

Melanoma-associated antigen A4 (MAGE-A4) is a Cancer/testis antigen (CTA) that interacts with the E3 ubiquitin Ligase RAD18 to enhance DNA damage tolerance in tumor cells. Here, we report the structure-guided optimization of a previously reported potent but cell-impermeable cyclic peptide, called MTP-1. Building off our previous peptide inhibitor efforts, we aimed to develop next-generation peptide inhibitors with significantly improved cell permeability. Through systematic structure-activity relationship (SAR) studies employing an mRNA display site-saturation mutagenesis library (SSML) and strategic scaffold optimization with modified cyclization strategy, we developed JWP24, the first cell-permeable peptide inhibitor of MAGE-A4. Evaluation across multiple assays demonstrates intracellular target engagement, maintained binding potency, and exhibits no cytotoxicity at effective concentrations. This study provides a valuable framework for transforming potent but larger, macrocyclic peptide inhibitors into cell-permeable probes. The work presented here demonstrates progress toward further establishing MAGE-A4 as a chemically tractable oncology target.

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