Discovery of Stapled Peptide MYC Degrader with Potent In Vivo Activities for Triple-Negative Breast Cancer Therapy.

Authors

Nan Zhang, Xin Li, Yunchen Xu, Yize Jiang, Songyan Gao, Huaxing Shen, Huang Li, Shuai Zhang, Guidong Chi, Bohan Ma, Hongli Liao, Honggang Hu, Si Chen, Xiang Li

Published in

Journal of medicinal chemistry. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

To target the "undruggable" oncoprotein MYC, we developed MAX-7, an (i, i+7) all-hydrocarbon stapled peptide designed to induce MYC degradation via the chaperone-mediated autophagy (CMA) pathway. Compared to its linear precursor, MAX-7 displays increased α-helicity, enhanced proteolytic stability, and excellent cell permeability. Mechanistically, MAX-7 drives potent, lysosome-dependent depletion of endogenous MYC, bypassing the ubiquitin-proteasome system. Consequently, MAX-7 suppresses proliferation, migration, and invasion while triggering apoptosis in triple-negative breast cancer (TNBC) cells. In vivo, MAX-7 administration achieves significant tumor regression in a 4T1 xenograft model with a favorable biosafety profile. This study validates stapled peptide-based CMA degraders as a powerful strategy to target "undruggable" intracellular drivers, highlighting MAX-7 as a promising therapeutic lead.

PMID:
42444318
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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