Stapled peptide MAX-7 degrades MYC via CMA, causing TNBC tumor regression in vivo
Background
The oncoprotein MYC is a critical driver of numerous malignancies, including triple-negative breast cancer (TNBC), promoting unchecked cell proliferation and altered gene expression. Despite its central role, MYC has historically been considered "undruggable" due to its intrinsically disordered nature, making it challenging to target with conventional small-molecule inhibitors. Current TNBC therapies often face limitations in efficacy and resistance development, highlighting an urgent need for novel therapeutic strategies. This study addresses the gap by exploring a stapled peptide approach to induce MYC degradation through the chaperone-mediated autophagy (CMA) pathway, offering a new avenue for targeting this difficult oncogene.
Study Design
Researchers developed MAX-7, an (i, i+7) all-hydrocarbon stapled peptide, as a novel MYC degrader. They compared MAX-7 to its linear precursor to evaluate α-helicity, proteolytic stability, and cell permeability. Mechanistically, they investigated its ability to induce MYC degradation via the chaperone-mediated autophagy (CMA) pathway, distinct from the ubiquitin-proteasome system, in TNBC cells. The peptide's impact on proliferation, migration, invasion, and apoptosis was assessed in TNBC cell lines. For in vivo efficacy, MAX-7 was administered to a 4T1 xenograft model, with tumor regression and biosafety profile as primary endpoints.
Results
MAX-7 demonstrated significantly increased α-helicity, enhanced proteolytic stability, and excellent cell permeability compared to its linear precursor, crucial properties for an intracellular therapeutic. Mechanistically, MAX-7 drove potent, lysosome-dependent depletion of endogenous MYC, uniquely bypassing the ubiquitin-proteasome system for degradation. This targeted MYC degradation led to a cascade of anti-cancer effects in TNBC cells. MAX-7 suppressed cell proliferation, migration, and invasion while triggering apoptosis. The most compelling finding was observed in vivo: > MAX-7 administration achieved significant tumor regression in a 4T1 xenograft model, demonstrating its therapeutic potential. Furthermore, the peptide exhibited a favorable biosafety profile, suggesting good tolerability.
Key Findings
- MAX-7, a stapled peptide, exhibits increased
α-helicity, enhancedproteolytic stability, and excellentcell permeability. - MAX-7 induces potent,
lysosome-dependent degradation of endogenousMYCviachaperone-mediated autophagy (CMA). - The peptide suppresses
proliferation,migration, andinvasionwhile triggeringapoptosisin TNBC cells. - In vivo, MAX-7 administration achieves significant tumor regression in a 4T1 xenograft model.
- MAX-7 demonstrates a favorable biosafety profile in the preclinical model.
Why It Matters
This research offers a groundbreaking strategy for targeting the notoriously "undruggable" MYC oncoprotein, particularly relevant for triple-negative breast cancer patients who often have limited treatment options. The validation of stapled peptide-based CMA degraders opens a new therapeutic modality for intracellular targets previously deemed inaccessible. MAX-7 represents a promising therapeutic lead, potentially transforming TNBC treatment by offering a novel mechanism to induce MYC degradation. While still in preclinical stages, this approach could pave the way for future clinical trials, potentially leading to more effective and less toxic treatments. The focus on lysosome-dependent degradation via CMA also highlights a new pathway for drug development, distinct from the more commonly targeted ubiquitin-proteasome system.
max-7
stapled-peptide
myc
tnbc
chaperone-mediated-autophagy
cancer