Uses
N-[1,1''-Biphenyl]-2-yl-7-nitro-2,1,3-benzoxadiazol-4-amine is a c-Myc inhibitor that suppresses its transcriptional activity.c-Myc is an oncoprotein often found overexpressed in various tumors.
General Description
A cell-permeable benzoxadiazole compound that is shown to preferentially disrupt the interactions of c-Myc-Max, Mad1-Max, and Myf5-HEB, over those of 31 other pairs of HLH-, ZIP-, and HLH-ZIP-containing proteins. Similarly to 10058-F4 (Cat. No. 475956), 10074-G5 is shown to selectively inhibit the c-Myc-dependent growth of rat fibroblast cell line TGR1 and effectively suppress c-Myc-dependent transcription activity. Binding studies using various mutated and truncated c-Myc constructs reveal that 10074-G5 targets c-Myc helix-1 region between aa 363 and 381 (KD = 4.4 μM), while 10058-F4 interaction site is located within aa residues 402 through 412 (KD = 13 μM).
Biological Activity
10074-g5 is a c-myc inhibitor [1].c-myc is a bhlh-zip transcription factor involved in cell cycle progression, cellular growth and metabolism, differentiation, and apoptosis. overexpression of c-myc has been identified in numerous cancers, including prostate, pancreatic, lung, breast, and colon cancers, b-cell lymphoma, and leukemias. alterations in c-myc have been associated with cancer aggressiveness and poor treatment prognosis. inhibition of c-myc is an attractive pharmacological approach in the development of new anticancer treatments. inactivation of c-myc rapidly results in cell-cycle arrest, apoptosis, tumor vascular degeneration, redifferentiation of tumor cells, and ultimately tumor regression [1].the ic50 values of 10074-g5 against daudi cells and hl-60 cells were 15.6 ± 1.5 μm and 13.5 ± 2.1 μm, respectively. 10074-g5 (10 μm) inhibited c-myc/max dimerization and decreased total c-myc protein expression. in c.b-17 scid mice bearing daudi xenografts, treatment with 10074-g5, (20 mg/kg i.v., for 10 consecutive days) significantly inhibited tumor growth with no effects on body weight.
Biochem/physiol Actions
10074-G5 is a c-Myc/Max interaction inhibitor. The c-Myc oncoprotein and its partner Max are intrinsically disordered (ID) monomers that undergo coupled folding and binding upon heterodimerization. 10074-G5, similarly to 10058-F4 (#F3680), specifically inhibits this interaction by binding to c-Myc, thus preventing C-Myc specific DNA binding and target genes regulation. 10074-G5 (2.8 microM) is slightly more potent that 10058-F4 (5.2 microM). It was discovered that 10074-G5 binds to a different specific binding site (region) of C-Myc than 10054-F4. Thus, the compound may become desirable for probing different interactions.
Synthesis
GENERAL METHOD: To a solution of 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl, 1 eq.) in acetonitrile (0.1 M) was added o-aminobiphenyl (1.1 eq.) followed by triethylamine (2 eq.). The reaction mixture was stirred at reflux for 16 hours under nitrogen protection. Upon completion of the reaction, the solvent was removed by rotary evaporator under reduced pressure. The residue was redissolved in ethyl acetate, washed sequentially with 1 M hydrochloric acid, water and saturated saline, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography with gradient elution using ethyl acetate/hexane mixed solvent.
in vivo
The plasma half-life of 10074-G5 in mice treated with 20 mg/kg i.v. is 37 min, and peak plasma concentration was 58 μM, which is 10-fold higher than peak tumor concentration[1].
References
[1] clausen d m, guo j, parise r a, et al. in vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of 10074-g5, a novel small-molecule inhibitor of c-myc/max dimerization[j]. journal of pharmacology and experimental therapeutics, 2010, 335(3): 715-727.
