2-氯-N,N-二乙基乙胺盐酸盐(CDEAH)对核碱基的烷基化作用可敏化 PARP1 缺失的肿瘤。

NAR Cancer Pub Date : 2023-08-07 eCollection Date: 2023-09-01 DOI:10.1093/narcan/zcad042
Minwoo Wie, Keon Woo Khim, Arnold S Groehler Iv, Soomin Heo, Junhyeok Woo, Kook Son, Eun A Lee, Jae Sun Ra, Sung You Hong, Orlando D Schärer, Jang Hyun Choi, Kyungjae Myung
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引用次数: 0

摘要

使用聚(ADP-核糖)聚合酶抑制剂(PARPi)通过合成致死来靶向 BRCA1 和 BRCA2 缺失的肿瘤,已成为一种成功的癌症治疗策略。PARPi 单药疗法在临床实践中显示出卓越的疗效和安全性,但受限于 BRCA 或其他同源重组基因的肿瘤基因组突变以及耐药性的快速出现。在这项研究中,我们发现2-氯-N,N-二乙基乙胺盐酸盐(CDEAH)是一种能选择性杀死PARP1-和A型色素性红斑狼疮缺陷细胞的小分子。CDEAH 是一种单功能烷化剂,可优先烷化鸟嘌呤核碱基,形成 DNA 加合物,这些加合物可通过 PARP1 依赖性碱基切除修复或核苷酸切除修复从 DNA 中清除。处理 PARP1 缺乏的细胞会导致链断裂的形成、S 期细胞的积累以及 DNA 损伤反应的激活。此外,与同源 PARP1 基因缺陷肿瘤相比,CDEAH 能选择性地抑制 PARP1 基因缺陷异种移植肿瘤的生长。总之,我们报告发现了一种诱导DNA损伤的烷化剂,它需要PARP1的活性来修复,并与PARPi协同作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Alkylation of nucleobases by 2-chloro-<i>N,N</i>-diethylethanamine hydrochloride (CDEAH) sensitizes <i>PARP1</i>-deficient tumors.

Alkylation of nucleobases by 2-chloro-<i>N,N</i>-diethylethanamine hydrochloride (CDEAH) sensitizes <i>PARP1</i>-deficient tumors.

Alkylation of nucleobases by 2-chloro-<i>N,N</i>-diethylethanamine hydrochloride (CDEAH) sensitizes <i>PARP1</i>-deficient tumors.

Alkylation of nucleobases by 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) sensitizes PARP1-deficient tumors.

Targeting BRCA1- and BRCA2-deficient tumors through synthetic lethality using poly(ADP-ribose) polymerase inhibitors (PARPi) has emerged as a successful strategy for cancer therapy. PARPi monotherapy has shown excellent efficacy and safety profiles in clinical practice but is limited by the need for tumor genome mutations in BRCA or other homologous recombination genes as well as the rapid emergence of resistance. In this study, we identified 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) as a small molecule that selectively kills PARP1- and xeroderma pigmentosum A-deficient cells. CDEAH is a monofunctional alkylating agent that preferentially alkylates guanine nucleobases, forming DNA adducts that can be removed from DNA by either a PARP1-dependent base excision repair or nucleotide excision repair. Treatment of PARP1-deficient cells leads to the formation of strand breaks, an accumulation of cells in S phase and activation of the DNA damage response. Furthermore, CDEAH selectively inhibits PARP1-deficient xenograft tumor growth compared to isogenic PARP1-proficient tumors. Collectively, we report the discovery of an alkylating agent inducing DNA damage that requires PARP1 activity for repair and acts synergistically with PARPi.

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