Myc plays important roles in cell cycle progression, cell growth, and stem cell self-renewal. Although dysregulation of Myc expression is a hallmark of human cancers, there is no Myc targeted therapy yet. Here, we report sAJM589, a novel small molecule Myc inhibitor, identified from a PCA-based high-throughput screen. sAJM589 potently disrupts the Myc-Max heterodimer in a dose dependent manner with an IC50 of 1.8 ± 0.03 μM. sAJM589 preferentially inhibits transcription of Myc target genes in a Burkitt lymphoma cell model, P493-6. Genome-wide transcriptome analysis showed that sAJM589 treatment and Myc depletion induced similar gene expression profiles. Consistently, sAJM589 suppressed cellular proliferation in diverse Myc-dependent cancer cell lines and anchorage independent growth of Raji cells. Disruption of the Myc-Max interaction by sAJM589 reduced Myc protein levels, possibly by promoting ubiquitination and degradation of Myc. Collectively, these results suggest that sAJM589 may be a basis for the development of potential inhibitors of Myc-dependent cell growth.