Structure-based design of new potent and highly selective PARP-1 inhibitor for treating colorectal cancer.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chunying Jiang, Shudan Yang, Yuting Wang, Liyuan Du, Miao-Miao Niu, Dongli Zhang
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引用次数: 0

Abstract

Poly (ADP-ribose) polymerase 1 (PARP-1) exhibits high expression levels in colorectal cancer (CRC) patients and participates in multiple DNA damage repair pathways, thereby emerging as an attractive target. Herein, we identified a series of PARP-1 inhibitors (termed as compounds 1-6) by pharmacophore modelling, virtual screening and biological evaluation. Enzyme inhibition assays demonstrated that compound-5 significantly inhibited PARP-1 activity (IC50 = 0.07 ± 0.01 nM) and exhibited high selectivity for PARP-1 among 63 different kinases. Molecular dynamic simulations indicated that compound-5 stably bound to the catalytic domain of PARP-1. Cellular assays demonstrated that compound-5 significantly inhibited the proliferation of a panel of human CRC cell lines (HCT116, SNU-1, Caco-2, HT-29). The data suggest that compound-5 may be a highly potent and selective PARP-1 inhibitor for CRC therapy.

基于结构的新型高效、高选择性PARP-1抑制剂治疗结直肠癌的设计。
聚(adp -核糖)聚合酶1 (PARP-1)在结直肠癌(CRC)患者中高表达,参与多种DNA损伤修复途径,因此成为一个有吸引力的靶点。在此,我们通过药效团模型、虚拟筛选和生物学评价确定了一系列PARP-1抑制剂(称为化合物1-6)。酶抑制实验表明,化合物-5显著抑制PARP-1活性(IC50 = 0.07±0.01 nM),对63种不同激酶的PARP-1具有较高的选择性。分子动力学模拟表明,化合物-5与PARP-1的催化结构域稳定结合。细胞实验表明,化合物-5显著抑制了一组人结直肠癌细胞系(HCT116、scn -1、Caco-2、HT-29)的增殖。这些数据表明,化合物-5可能是一种高效、选择性的PARP-1抑制剂,可用于结直肠癌治疗。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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