flap内切核酸酶1抑制剂的N-羟基脲系列的鉴定与优化

The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors.

作者信息

Tumey L Nathan, Bom David, Huck Bayard, Gleason Elizabeth, Wang Jianmin, Silver Daniel, Brunden Kurt, Boozer Sherry, Rundlett Stephen, Sherf Bruce, Murphy Steven, Dent Tom, Leventhal Christina, Bailey Andrew, Harrington John, Bennani Youssef L

机构信息

Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA.

出版信息

Bioorg Med Chem Lett. 2005 Jan 17;15(2):277-81. doi: 10.1016/j.bmcl.2004.10.086.

DOI:10.1016/j.bmcl.2004.10.086

PMID:15603939

Abstract

Flap endonuclease-1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. Sensitization to DNA damaging agents is a potential method for the improvement of the therapeutic window of traditional chemotherapeutics. In this paper, we describe the identification and SAR of a series of low nanomolar FEN1 inhibitors. Over 1000-fold specificity was achieved against a related endonuclease, xeroderma pigmentosum G (XPG). Two compounds from this series significantly potentiate the action of methyl methanesulfonate (MMS) and temozolamide in a bladder cancer cell line (T24). To our knowledge, these are the most potent endonuclease inhibitors reported to date.

摘要

瓣内切核酸酶-1（FEN1）是参与碱基切除修复（BER）的关键酶，BER是哺乳动物细胞用于修复DNA损伤的主要途径。对DNA损伤剂敏感是改善传统化疗药物治疗窗口的一种潜在方法。在本文中，我们描述了一系列低纳摩尔FEN1抑制剂的鉴定和构效关系。对相关内切核酸酶——着色性干皮病G（XPG）实现了超过1000倍的特异性。该系列中的两种化合物在膀胱癌细胞系（T24）中显著增强了甲磺酸甲酯（MMS）和替莫唑胺的作用。据我们所知，这些是迄今为止报道的最有效的内切核酸酶抑制剂。