Pharmacophore identification of c-Myc inhibitor 10074-G5

Abstract

A structure-activity relationship (SAR) of the c-Myc (Myc) inhibitor 10074-G5 (N-([1,1′-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine, 1), which targets a hydrophobic domain of Myc that is flanked by arginine residues, was executed in order to determine its pharmacophore. Whilst the 7-nitrobenzofurazan was found to be critical for inhibitory activity, the ortho-biphenyl could be replaced with a para-carboxyphenyl group to furnish the new inhibitor JY-3-094 (3q). Around five times as potent as the lead with a IC50 of 33 μM for disruption of the Myc–Max heterodimer, JY-3-094 demonstrated excellent selectivity over Max–Max homodimers, with no apparent effect at 100 μM. Importantly, the carboxylic acid of JY-3-094 improves the physicochemical properties of the lead compound, which will facilitate the incorporation of additional hydrophobicity that might enhance Myc inhibitory activity further still.

Perturbation of the c-Myc–Max Protein–Protein Interaction via Synthetic α-Helix Mimetics

“…34 However, they are relatively inefficient at disrupting pre-formed dimers due to the high free energy of protein–protein association. 34–38,45–49 An experimental outcome consistent with this previously proposed model is shown in Figure 4. After first establishing conditions under which c-Myc–Max(S) heterodimer binding to an E-box-containing oligonucleotide could be quantified (Figure 4A), we showed that 2 prevented c-Myc–Max(S) oligonucleotide binding significantly better if it was pre-incubated with c-Myc monomer prior to the addition of Max(S) (Figure 4B vs. 4C).…”

“…37,38,45,48,49 As shown in Table 5, all compounds except 21 inhibited the proliferation of both cell lines with IC 50 s below 50 µM. Indeed, the HL60 inhibition data closely mirrored the in vitro data for inhibition of the c-Myc–Max(S)/DNA ternary complex.…”

“…34–49 Several of the more potent compounds that have been identified bind to distinct segments of this region and cause highly localized distortions that prevent productive interaction with Max’s bHLH-ZIP domain. 45,46 For example, 10058-F4 ( 1 ) binds c-Myc 402–410 , whilst 10074-G5 ( 2 ) binds c-Myc 363–381 . However, these compounds generally exhibit only low affinities to c-Myc, double-digit micromolar IC 50 values for the prevention of c-Myc–Max heterodimerization in vitro and similar activities in cellular proliferation assays.…”

Small-molecule inhibitors of the Myc oncoprotein

“…Yap et al (144) conducted a structure–activity relationship analysis of 10074-G5 in which the NMR model of its Myc binding site was used as a guide. The electron-rich nitro group and furazan ring were found to be critical to Myc inhibitory activity, which is consistent with these groups binding the basic residues R366, R367 and R372 as proposed above.…”

Therapeutic Strategies to Inhibit MYC

“…These and other studies have led to a list of structurally diverse compounds with reported activity against the MYC:MAX:DNA-binding event ( Fig. 2) (Yap et al 2013). …”