Pharmacophore Identification of c-Myc Inhibitor 10074-G5

Jeremy L Yap, Huabo Wang, Angela Hu, Jay Chauhan, Kwan-Young Jung, Robert B Gharavi, Edward V Prochownik, Steven Fletcher

Bioorg Med Chem Lett. 2013 Jan 1;23(1):370-4.

PMID: 23177256

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP413611935-A	10074-G5		413611-93-5	Price