Discovery of a Pyrazolopyridinone-Based MYC Inhibitor That Selectively Engages Intracellular c‑MYC and Disrupts MYC–MAX Heterodimerization

c-MYC is an oncogenic transcription factor that plays a crucial role in the regulation of downstream targets involved in proliferation, apoptosis, differentiation, metabolism, signaling, and immune response processes whose deregulation leads to the progression of different pathologies. The development of selective and potent small-molecule inhibitors of c-MYC remains a grand challenge in chemical biology and medicine due to its undruggability, derived from extensive intrinsic disorder. In this study, we identified a novel dihydro pyrazolo pyridinone scaffold, MY05, that selectively targets c-MYC in cells and disrupts MYC–MAX interaction. MY05 engages intracellular c-MYC, modulates c-MYC thermal stability, reduces c-MYC transcriptional targets, and inhibits proliferation in cancer cells and tumor growth in mice. In summary, we identified a novel compound that directly interacts with c-MYC to disrupt the transcriptional program.