RT Journal Article
SR Electronic
T1 P6981, an Arylstibonic Acid, is a Novel Low Nanomolar Inhibitor of CREB binding to DNA
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.080820
DO 10.1124/mol.112.080820
A1 Jianfei Zhao
A1 Jason R Stagno
A1 Lyuba Varticovski
A1 Eric Nimako
A1 Vikas Rishi
A1 Kathy McKinnon
A1 Rhone Akee
A1 Robert H Shoemaker
A1 Xinhua Ji
A1 Charles Vinson
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/07/31/mol.112.080820.abstract
AB Several B-ZIP transcription factors have been implicated in cancer, substance abuse, and other pathological conditions. We previously identified arylstibonic acids that bind to B-ZIP proteins and inhibit their interaction with DNA. In this study, we used EMSA to analyze 46 arylstibonic acids for their activity to disrupt the DNA binding of three B-ZIP (C/EBPα, CREB and VBP) and two B-HLH-ZIP (USF and Mitf) proteins. 25 arylstibonic acids showed activity at micromolar concentrations. The most active compound, P6981, had half-maximal inhibition at ~5 nM for CREB. Circular dichroism thermal denaturation studies indicated that P6981 binds both the B-ZIP domain and the leucine zipper. The crystal structure of an arylstibonic acid, NSC13778, bound to the VBP leucine zipper identified electrostatic interactions between both the stibonic and carboxylic acid groups of NSC13778 and arginine side-chains of VBP that is also involved in interhelical salt bridges in the leucine zipper. P6981 induced GFP-B-ZIP chimeric proteins to partially localize to the cytoplasm, demonstrating that it is active in cells. P6981 inhibited the growth of a patient-derived clear cell sarcoma cell line, whose oncogenic potential is driven by a chimeric protein EWS-ATF1 which contains the DNA binding domain of ATF1, a B-ZIP protein. NSC13778 inhibited the growth of xenografted clear cell sarcoma and no toxicity was observed. These experiments suggest that antimony containing arylstibonic acids are promising leads for suppression of DNA binding activities of B-ZIP and B-HLH-ZIP transcription factors.