Alternative Strategies of Reducing MYC Expression for the Treatment of Cancers.

MYC is a master oncogene regulating cell proliferation, differentiation, cell cycle, metabolism, and apoptosis, which is implicated in nearly 70% of human cancers. Targeting MYC dysregulation represents a promising therapeutical strategy for cancer treatment; however, no direct MYC-targeting agents have been approved for clinical use. This is largely attributed to the intrinsically disordered structure and nuclear localization of MYC, which complicate direct-targeting. Consequently, there has been growing interest in indirect regulatory strategies for MYC-driven cancers. Meanwhile, PROTAC has emerged as an effective approach against "undruggable" transcription factors like MYC. For this reason, this perspective summarizes MYC's structure and biological functions, examines cancer progression driven by its dysregulation, and evaluates current therapeutic strategies. We focus on three innovative strategies: (1) recently developed dual-targeted agents that suppress MYC expression, (2) aptamer-based PROTACs for direct MYC degradation, and (3) indirect MYC-targeting PROTAC platforms. We provide critical insights for developing therapeutics against MYC-driven cancers.