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Bioorg Med Chem Lett. 2013 Jan 1;23(1):370-4. doi: 10.1016/j.bmcl.2012.10.013. Epub 2012 Oct 17.

Pharmacophore identification of c-Myc inhibitor 10074-G5.

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1
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine St, Baltimore, MD 21201, USA.

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 IC(50) 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.

PMID:
23177256
PMCID:
PMC3525812
DOI:
10.1016/j.bmcl.2012.10.013
[Indexed for MEDLINE]
Free PMC Article
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