Abstract 4284: Determining selectivity of MYC inhibitors via transcriptional monitoring of sentinel genes

Abstract MYC is a key transcription factor with essential roles in development and tissue maintenance. Deregulation of MYC has been described in many cancers and several MYC inhibitors have been published, but their selectivity has often remained unclear. A key challenge is the short half-life of MYC mRNA and protein, making MYC particularly sensitive to general transcriptional and translational stress. Therefore, discrimination between on- and off-target effects on MYC and its transcriptional output is critical. Here, we used SLAMseq-derived direct target genes of MYC to establish a panel of sentinel genes to quantify direct and selective effects on MYC. Changes in transcriptional output of MYC are measurable within a few hours after various treatments and can discriminate between on-target MYC perturbation and off-target cytotoxic effects. We then used the assay to benchmark selectivity of various pre-clinical MYC inhibitors. Importantly, the assay principle can be transferred to other important transcription factor drug targets. Citation Format: Susanne Stockinger, Sabine Hartl, Manfred Koegl, Johannes Zuber, Matthias Samwer. Determining selectivity of MYC inhibitors via transcriptional monitoring of sentinel genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4284.