当前位置:科学网首页 > 小柯机器人 >详情
研究发现一种可改善化疗效果的小分子
作者:小柯机器人 发布时间:2019/7/27 20:16:29

美国杜克大学医学中心Pei Zhou研究小组,发现一个小分子能够靶向诱变性跨损伤合成并改善化疗药效。这一研究成果发表在2019年6月6日出版的国际学术期刊《细胞》上。

研究人员发现了一种小分子抑制剂:JH-RE-06,通过阻碍诱变聚合酶ζ的募集而破坏诱变性TLS。值得注意的是,JH-RE-06靶向REV1几乎无特征的表面,该表面与聚合酶ζ的REV7亚基相互作用。JH-RE-06的结合诱导REV1二聚化,阻碍了REV1-REV7相互作用和聚合酶ζ的募集。对于培养人及小鼠细胞系,JH-RE-06能够抑制突变性TLS,并增强顺铂诱导的毒性。联合应用JH-RE-06和顺铂抑制小鼠内异种移植人黑素瘤的生长。该研究为开发TLS抑制剂,并使其成为一类新型的化疗佐剂奠定了基础。

据了解,固有和获得性耐药性,以及继发性恶性肿瘤的诱导,这些因素使得化疗难以成功。由于诱变性跨损伤合成(TLS)有助于提高化疗耐药性和治疗诱导的突变,靶向TLS是一种很有吸引力的改善化疗途径。然而,开发具有高特异性和体内药效的小分子用于诱变性TLS一直是一个挑战。

附:英文原文

Title: A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy

Author: Jessica L. Wojtaszek, Nimrat Chatterjee, Javaria Najeeb, Azucena Ramos, Minhee Lee, Ke Bian, Jenny Y. Xue, Benjamin A. Fenton, Hyeri Park, Deyu Li, Michael T. Hemann, Jiyong Hong, Graham C. Walker, Pei Zhou

Issue&Volume: Jun 27, 2019 Volume 178Issue 1

Abstract: Intrinsic and acquired drug resistance and induction of secondary malignancies limit successful chemotherapy. Because mutagenic translesion synthesis (TLS) contributes to chemoresistance as well as treatment-induced mutations, targeting TLS is an attractive avenue for improving chemotherapeutics. However, development of small molecules with high specificity and in vivo efficacy for mutagenic TLS has been challenging. Here, we report the discovery of a small-molecule inhibitor, JH-RE-06, that disrupts mutagenic TLS by preventing recruitment of mutagenic POL ζ. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL ζ. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL ζ recruitment. JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced toxicity in cultured human and mouse cell lines. Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft human melanomas in mice, establishing a framework for developing TLS inhibitors as a novel class of chemotherapy adjuvants.

DOI: https://doi.org/10.1016/j.cell.2019.05.028

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30556-2

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/