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