Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10596242 | Bioorganic & Medicinal Chemistry Letters | 2013 | 5 Pages |
Abstract
A structure-activity relationship (SAR) study of the c-Myc (Myc) inhibitor 10074-G5 (N-([1,1â²-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.
Keywords
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Jeremy L. Yap, Huabo Wang, Angela Hu, Jay Chauhan, Kwan-Young Jung, Robert B. Gharavi, Edward V. Prochownik, Steven Fletcher,