Targeted Disruption of Myc–Max Oncoprotein Complex by a Small Molecule

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.