The transcription factor c-MYC is a promising, but challenging target deregulated in ~70% of human cancers. We utilized high-throughput screens to identify KI-MS2 as a small molecule binder of MAX, the obligate protein partner of c-MYC. In cells, KI-MS2 treatment modulated c-MYC transcriptional activity, inhibited cell viability in a c-MYC-dependent manner, and mimicked c-MYC inactivation. Additionally, KI-MS2 suppressed the growth of c-MYC-driven tumors in mouse models.

Here we report the design, construction and characterization of extracellularly regulated synthetic RNA circuits in mammalian cells. We created small molecule-responsive RNA binding proteins and other tunable circuit components to build inducible genetic switches using both modified and self-amplifying RNA. Our approach enables precise extracellular control over gene expression, advancing the therapeutic potential of RNA as a platform for gene therapy.