c-Myc is a basic helix-loop-helix-leucine zipper (bHLH-ZIP) transcription factor 
that is responsible for the transcription of a wide range of target genes 
involved in many cancer-related cellular processes. Over-expression of c-Myc has 
been observed in, and directly contributes to, a variety of human cancers 
including those of the hematopoietic system, lung, prostate and colon. To become 
transcriptionally active, c-Myc must first dimerize with Myc-associated factor X 
(Max) via its own bHLH-ZIP domain. A proven strategy towards the inhibition of 
c-Myc oncogenic activity is to interfere with the structural integrity of the 
c-Myc-Max heterodimer. The small molecule 10074-G5 is an inhibitor of c-Myc-Max 
dimerization (IC50 =146 μM) that operates by binding and stabilizing c-Myc in 
its monomeric form. We have identified a congener of 10074-G5, termed 3jc48-3 
(methyl 
4'-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1'-biphenyl]-3-carboxylate), 
that is about five times as potent (IC50 =34 μM) at inhibiting c-Myc-Max 
dimerization as the parent compound. 3jc48-3 exhibited an approximate twofold 
selectivity for c-Myc-Max heterodimers over Max-Max homodimers, suggesting that 
its mode of action is through binding c-Myc. 3jc48-3 inhibited the proliferation 
of c-Myc-over-expressing HL60 and Daudi cells with single-digit micromolar IC50 
values by causing growth arrest at the G0 /G1 phase. Co-immunoprecipitation 
studies indicated that 3jc48-3 inhibits c-Myc-Max dimerization in cells, which 
was further substantiated by the specific silencing of a c-Myc-driven luciferase 
reporter gene. Finally, 3jc48-3's intracellular half-life was >17 h. 
Collectively, these data demonstrate 3jc48-3 to be one of the most potent, 
cellularly active and stable c-Myc inhibitors reported to date.