Chemical Induction of MYC Protein Degradation via MYC-MAX Disruption and 20S Proteasome Activation

The MYC oncoprotein is a master regulator of cell growth and transcriptional amplification and is aberrantly overexpressed in a broad spectrum of human cancers, including colorectal carcinoma. Despite its central role in tumorigenesis, MYC has remained pharmacologically intractable due to its intrinsically disordered architecture, which lacks persistent small-molecule binding pockets. Here, we report a chemical biology strategy that exploits MYC's structural disorder as a therapeutic vulnerability. By combining small-molecule disruption of the MYC-MAX protein-protein interaction with pharmacological activation of the 20S proteasome, we induce rapid and pronounced depletion of MYC in MYC-dependent colorectal cancer cell lines. MYC loss is proteasome-dependent and persists following knockdown of FBXW7, indicating a degradation mechanism distinct from canonical SCF-FBXW7-mediated turnover and consistent with direct 20S proteasomal degradation. Dual treatment also suppresses MYC-driven transcriptional programs and significantly enhances apoptotic cell death. Collectively, these findings establish a framework in which protein-protein interaction inhibition sensitizes intrinsically disordered oncoproteins to 20S proteasome-mediated degradation. This work expands the therapeutic landscape for MYC-driven malignancies and highlights proteasome activation as a complementary strategy for targeting structurally disordered cancer drivers.