c-Myc is a proto-oncogenic transcription factor that is dysregulated in most, perhaps all, human cancers, and contributes to both the development and progression of the disease. Until recently, considerable skepticism was held towards the inhibition of c-Myc as an anti-tumour strategy given the significant role of c-Myc in various key processes, such as proliferation, differentiation and apoptosis, in normal cells. However, the apparent narrow therapeutic window of c-Myc has been widened thanks to the revelation that c-Myc does not turn on and off the transcription of target genes, as was previously thought. Rather, c-Myc acts as an �amplifier�, elevating or depressing transcription of genes that have already become transcriptionally activated. Intrinsically disordered in the monomeric state, c-Myc, a member of the basic helix-loop-helix-leucine zipper (bHLH-ZIP) family, provides little opportunity for targeted drug design, which is likely one reason why no �c-Myc drug� has entered the clinic. Nevertheless, a chemically diverse group of small-molecules has been identified that inhibit the obligatory dimerization of c-Myc with the bHLH-ZIP family member Max. Beginning with c-Myc inhibitor 10074-G5 (N-([1,1'-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine), a structure-activity relationship study led to the discovery of JY-3-094 (4-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)benzoic acid), which exhibits almost a five-fold improvement in the inhibition of c-Myc�Max dimerization (IC50 = 33 �M vs. 146 �M). Current efforts towards the further optimization of JY-3-094 include the introduction of bioisosteric replacements of the nitro group and the carboxylic acid function, both of which will improve metabolic stability, promote cell penetration and enhance c-Myc�Max inhibitory activity.

Towards novel anti-cancer therapeutics: Pharmacologic inhibitors of c-Myc�Max dimerization

247th National Meeting (2014)

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