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.