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 (K
D = 4.4 μM), while 10058-F4 interaction site is located within aa residues 402 through 412 (K
D = 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.
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.
