Pharmacophore identification of c-Myc inhibitor 10074-G5

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Abstract

A structure–activity relationship (SAR) study 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 the Myc oncoprotein 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 an 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.

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Acknowledgments

Financial support for this work is gratefully acknowledged from the University of Maryland School of Pharmacy (SF), an American Chemical Society Pre-Doctoral Medicinal Chemistry Fellowship (JLY) and NIH grant R01 CA140624 (EVP).

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      Computational structure similarity searching for compounds in which the 6-membered ethylbenzylidene and five-membered rhodanine rings of 10058-F4 were varied has led to synthetic derivative #474, which exhibits a 10-fold improvement of potency [114]. Pharmacore analysis of 10074-G5 determined the nitro and oxadiazole moieties of the benzofuran derivative to be essential for inhibitory activity against MYC heterodimerization [115]. Analogue JY-3-094, in which the biphenyl group has been replaced by para-substituted benzoic acid, shows a 10-fold improvement in potency (as assessed by electrophoretic mobility shift assay (EMSA)) but poor cellular uptake in HL-60 cells.

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      Thus, c-Myc inhibitors could help to suppress the initiation and progression of tumors. Recently, lots of c-Myc inhibitors were discovered including Myc-Max protein-protein interactions [17–19], such as 10058-F4, 10074-G5, SF-4-017, NUCC-0176242, or Myc-Max protein-DNA binding interactions [20,21], such as Mycro 3, KJ Pyr 9, or binding to c-Myc G-quadruplex(G4) stabilizers [22,23], such as Indenoisoquinoline 5, IZCZ-3, etc. Despite plenty of c-Myc inhibitors (shown in Fig. 1) reported, there is no anti-Myc drug clinically available.

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    These authors contributed equally to this work.

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