Abstract
Abstract Inhibition of the DNA damage checkpoint and repair functions is a promising approach to improve chemosensitivity. Ataxia telangiectasia and Rad3-related protein (ATR) is an important checkpoint kianse responsible for organizing both normal and stressful DNA replication. In previous, we discovered a natural compound protoapigenone (WYC02) and its synthetic derivate WYC0209 are able to inhibit ATR-mediated Chk1 phosphorylation, impair the G2/M checkpoint, and improve cancer sensitivity to cisplatin both in vitro and in vivo. Although all evidences convince ATR signaling is disrupted by WYC compounds, the effect of compounds on ATR kinase activity is still unknown. In this study, we further provide evidences to prove that WYC02 and WYC0209 are undoubted ATR inhibitors by using of in vitro kinase assay. The data showed WYC0209 inhibits ATR kinase activity at least 4 times greater than WYC02, and enhances MDA-MB-231cells sensitivity to DNA replication-affecting agents such as doxorubicin, mitomycin C, and etoposide, but has little or no effect to mitosis-affecting microtubule inhibitor palcitaxol. The result of this study proposes a strategy to improve most of current chemotherapeutics in which aim to selective disrupting DNA replication in fast growing cancers. Citation Format: Hui-Chun Wang, Alan Yueh-Luen Lee, Chin-Chung Wu, Yang-Chang Wu. Discovery of ATR kinase inhibitors from natural products. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1637. doi:10.1158/1538-7445.AM2014-1637
Published Version
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