title: Pharmacophore identification of c-Myc inhibitor 10074-G5.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine St, Baltimore, MD 21201, USA.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Yap
authors.forename: Huabo
authors.initials: H
authors.lastname: Wang
authors.forename: Angela
authors.initials: A
authors.lastname: Hu
authors.forename: Jay
authors.initials: J
authors.lastname: Chauhan
authors.forename: Kwan-Young
authors.initials: KY
authors.lastname: Jung
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gharavi
authors.forename: Edward V
authors.initials: EV
authors.lastname: Prochownik
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
mesh_terms: D001665:Binding Sites; D019281:Dimerization; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C534883:10074-G5; D010069:Oxadiazoles; D016271:Proto-Oncogene Proteins c-myc