12 Arylstibonic acids that inhibit the DNA binding of five B-ZIP dimers

Abstract

Previously, we identified an arylstibonic acid, NSC13778 that specifically binds to the basic region of the C/EBPalpha B-ZIP domain and disrupts DNA binding. We now examine a panel of 14 additional arylstibonic acid derivatives of NSC13778 for their ability to inhibit the DNA binding of five B-ZIP dimers (c-Fos|JunD, VBP, C/EBPalpha, C/EBPbeta, and CREB). They show various specificities at inhibiting the DNA binding of five B-ZIP domains. NSC13746 inhibits the DNA binding of C/EBPbeta and CREB at 100nM and promiscuously inhibiting the DNA binding of all five proteins in the 1muM range. Dialysis experiments indicate that NSC 13746 binding to the B-ZIP domain is reversible. Thermal denaturation studies indicate that NSC13746 binds the B-ZIP domain. Some compounds specifically inhibit DNA binding, with VBP and c-Fos|JunD being most easily disrupted. These compounds inhibit, with similar specificities to the pure B-ZIP domains, the DNA binding of nuclear extract to the AP1 DNA sequence but no inhibition is observed to SP1 containing oligonucleotide. Transient transfection assays indicate that NSC13746 can inhibit the TPA induced activation of two B-ZIP dependent reporters. These experiments suggest that arylstibonic acids are promising leads for inhibiting the DNA binding of a group of B-ZIP proteins in cells.

Anti-cancer effect of snake venom toxin through down regulation of AP-1 mediated PRDX6 expression

“…Other studies demonstrated that direct interaction of cyclopentenone 15-deoxy- Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) with 269 cysteine of AP-1 protein, and thus contribute to the complex effects of 15d-PGJ 2 on the cellular response to pro-inflammatory agents [ 56 ]. Arylstibonic acid NSC13746 binds specifically to c-Fos/JunD dimer of B-ZIP proteins at micromolar concentrations and can inhibit their DNA-binding activity both in vitro and in vivo [ 57 ]. Expression in the mouse epidermis of A-Fos, a dominant negative form that inhibits AP-1 DNA binding, converts papillomas into benign sebaceous adenomas that are not able to convert into carcinomas [ 58 ].…”

Pathological Unfoldomics of Uncontrolled Chaos: Intrinsically Disordered Proteins and Human Diseases

“…Further screening of stibonic acids identified additional very active but promiscuous inhibitors of bZip (CREB) and bHLHZip (USF and Mitf) proteins. 297,298 Rudenko and co-workers 299 screened 54 498 molecules for inhibitors of ΔFosB DNA binding. They identified two, C2 and C6, that were active in follow-up assays.…”

P6981, An Arylstibonic Acid, Is a Novel Low Nanomolar Inhibitor of cAMP Response Element-Binding Protein Binding to DNA

“…All other proteins used in this study have been described previously, including C/EBP␣ (Krylov et al, 1995), C/EBP␤ (Rishi et al, 2005), CREB (Ahn et al, 1998), CREB-LZ (Ahn et al, 1998), VBP (Moll et al, 2000), VBP-LZ (Moll et al, 2000), Mitf (Rishi et al, 2004), and USF (Rishi et al, 2004). The recombinant proteins were overexpressed in the Escherichia coli BL21 (LysE) strain and purified as described previously (Krylov et al, 1995;Olive et al, 1997;Rishi et al, 2010).…”