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
  • 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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