Design and activity of AP endonuclease-1 inhibitors

Journal of Chemical Biology

Paul A. Johnston¹  LiRong Wang¹  Abdulrahman A. Almehizia¹  David Close¹  Stanton Kochanek¹  Zhiwei Feng¹  Barry Gold¹  Ajay Srinivasan¹  Xiang-Qun Xie¹  Prema Iyer¹ 

[1] Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261 USA

关键词: AP endonuclease;    Abasic sites;    DNA repair;    Drug synergy;    Toxicity;   

DOI  :  10.1007/s12154-015-0131-7

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

Apurinic/apyrimidinic endonuclease-1/redox effector factor-1 (APE-1) is a critical component of base excision repair that excises abasic lesions created enzymatically by the action of DNA glycosylases on modified bases and non-enzymatically by hydrolytic depurination/depyrimidination of nucleobases. Many anticancer drugs generate DNA adducts that are processed by base excision repair, and tumor resistance is frequently associated with enhanced APE-1 expression. Accordingly, APE-1 is a potential therapeutic target to treat cancer. Using computational approaches and the high resolution structure of APE-1, we developed a 5-point pharmacophore model for APE-1 small molecule inhibitors. One of the nM APE-1 inhibitors (AJAY-4) that was identified based on this model exhibited an overall median growth inhibition (GI50) of 4.19 μM in the NCI-60 cell line panel. The mechanism of action is shown to be related to the buildup of abasic sites that cause PARP activation and PARP cleavage, and the activation of caspase-3 and caspase-7, which is consistent with cell death by apoptosis. In a drug combination growth inhibition screen conducted in 10 randomly selected NCI-60 cell lines and with 20 clinically used non-genotoxic anticancer drugs, a synergy was flagged in the SK-MEL-5 melanoma cell line exposed to combinations of vemurafenib, which targets melanoma cells with V600E mutated BRAF, and AJAY-4, our most potent APE-1 inhibitor. The synergy between AJAY-4 and vemurafenib was not observed in cell lines expressing wild-type B-Raf protein. This synergistic combination may provide a solution to the resistance that develops in tumors treated with B-Raf-targeting drugs.

【 授权许可】

Unknown