- POTENT ANALOGUES OF THE C-MYC INHIBITOR 10074-G5 WITH IMPROVED CELL PERMEABILITY
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The present invention relates compounds and compositions for interfering with the association of Myc and Max. These compounds and compositions are useful in methods for inhibiting growth or proliferation of a cell. Methods of inhibiting growth or proliferation of a cell comprise contacting the cell with an amount of a compound that interferes with Myc and Max association effective to inhibit growth or proliferation of the cell. The compounds exhibit increased inhibitory activity against c-Myc relative to the known c-Myc inhibitor small-molecule benzofurazan N-([1,1′-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine (10074-G5).
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Paragraph 0078; 0079; 0083
(2014/10/16)
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- Pharmacophore identification of c-Myc inhibitor 10074-G5
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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.
- Yap, Jeremy L.,Wang, Huabo,Hu, Angela,Chauhan, Jay,Jung, Kwan-Young,Gharavi, Robert B.,Prochownik, Edward V.,Fletcher, Steven
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supporting information
p. 370 - 374
(2013/02/23)
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- Derivatization of Amines with 4-Substituted 7-Nitrobenzofurazans
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Electrophilic derivatives of 4-nitro-benzofurazan with different reactivities were used to synthesize 28 new mono- and disubstituted 4-amino-7-nitrobenzofurazans 2b, 2d, 2f-2i, 2l, 2m-2n, 3b-3f, 3h-3j, 4c-4d, 4f-4k, 4m, 4o-4p.A reaction mechanism is proposed on the basis of the differences of the reactivities and a preliminary kinetic examination.The acid character of the N-H-function in monosubstituted compounds is demonstrated by means of spectroscopical investigation of pKa-values.Data from i.r., u.v./vis, and fluorescence studies are offered.
- Heberer, H.,Kersting, H.,Matschiner, H.
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p. 487 - 504
(2007/10/02)
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