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新型 ATR/PARP1 双重抑制剂在三阴性乳腺癌模型中显示出协同抗肿瘤疗效。

Novel ATR/PARP1 Dual Inhibitors Demonstrate Synergistic Antitumor Efficacy in Triple-Negative Breast Cancer Models.

作者信息

Gao Yuan, Zhou Jiawei, Wang Chen-Chen, Wang Zong-Hao, Mao Nian-Dong, He Meng-Lan, Zhang Peng-Peng, Huang Ping, Ye Guo-Wei, Zhang Yu-Qing, Tang Feng-Hui, Zhang Hang, Xie Tian, Ye Xiang-Yang

机构信息

Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang Province, 310000, China.

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310000, China.

出版信息

Adv Sci (Weinh). 2025 Aug;12(29):e01916. doi: 10.1002/advs.202501916. Epub 2025 Jun 16.

DOI:10.1002/advs.202501916
PMID:40521858
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12362783/
Abstract

Concomitant inhibition of ataxia telangiectasia and Rad3-related protein (ATR) and poly ADP-ribose Polymerase (PARP) pathways is a promising strategy in cancer therapy, potentially expanding the clinical utility of ATR inhibitor (ATRi) and PARP inhibitor (PARPi). A novel series of ATR/PARP1 dual inhibitors is developed through the pharmacophore fusion of AZD6738 and Olaparib. Among them, B8 emerges as the most promising candidate, exhibiting potent ATR (IC: 17.3 nM) and PARP1 (IC: 0.38 nM) inhibition. B8 effectively reduced cell viability, induced apoptosis, and caused G2/M cell cycle arrest in TNBC cells. Additionally, B8 significantly impaired TNBC colony formation, migration, and invasion. Mechanistically, B8 induces DNA damage, evidenced by increased γH2AX levels. In in vivo studies, B8 suppressed tumor growth more effectively than the combination in MDA-MB-468 xenografted mice, with no significant body weight loss. B8 also enhanced γH2AX expression in tumor tissues. These findings confirm the synergistic effects of ATR/PARP1 co-inhibition and highlight the potential of this novel inhibitor class for TNBC therapy.

摘要

同时抑制共济失调毛细血管扩张症突变基因（ATM）和Rad3相关蛋白（ATR）以及聚ADP核糖聚合酶（PARP）信号通路是一种很有前景的癌症治疗策略，可能会扩大ATR抑制剂（ATRi）和PARP抑制剂（PARPi）的临床应用。通过将AZD6738和奥拉帕利进行药效团融合，开发出了一系列新型的ATR/PARP1双重抑制剂。其中，B8成为最有前景的候选药物，对ATR（IC：17.3 nM）和PARP1（IC：0.38 nM）具有强效抑制作用。B8有效降低了三阴性乳腺癌（TNBC）细胞的活力，诱导细胞凋亡，并导致G2/M期细胞周期阻滞。此外，B8显著损害了TNBC细胞的集落形成、迁移和侵袭能力。从机制上讲，B8诱导了DNA损伤，γH2AX水平升高证明了这一点。在体内研究中，B8在MDA-MB-468异种移植小鼠中比联合用药更有效地抑制了肿瘤生长，且体重没有显著下降。B8还增强了肿瘤组织中γH2AX的表达。这些发现证实了ATR/PARP1共同抑制的协同作用，并突出了这类新型抑制剂在TNBC治疗中的潜力。

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2
Effect of Androgen receptors in Triple-Negative Breast Cancer Given Neoadjuvant Therapy: A Systematic Review and Meta-Analysis.雄激素受体在接受新辅助治疗的三阴性乳腺癌中的作用：一项系统评价和荟萃分析
Asian Pac J Cancer Prev. 2024 Dec 1;25(12):4115-4122. doi: 10.31557/APJCP.2024.25.12.4115.
3
The Potential of PARP Inhibitors as Antitumor Drugs and the Perspective of Molecular Design.
聚（ADP-核糖）聚合酶（PARP）抑制剂作为抗肿瘤药物的潜力及分子设计前景
J Med Chem. 2025 Jan 9;68(1):18-48. doi: 10.1021/acs.jmedchem.4c02642. Epub 2024 Dec 26.
4
Trametinib and M17, a novel small molecule inhibitor of AKT, display a synergistic antitumor effect in triple negative breast cancer cells through the AKT/mTOR and MEK/ERK pathways.曲美替尼和M17（一种新型的AKT小分子抑制剂）通过AKT/mTOR和MEK/ERK途径在三阴性乳腺癌细胞中显示出协同抗肿瘤作用。
Bioorg Chem. 2025 Jan;154:107981. doi: 10.1016/j.bioorg.2024.107981. Epub 2024 Nov 22.
5
Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms.PARP抑制剂在BRCA突变三阴性乳腺癌中的联合策略：克服耐药机制
Oncogene. 2025 Feb;44(4):193-207. doi: 10.1038/s41388-024-03227-6. Epub 2024 Nov 21.
6
Update on Combination Strategies of PARP Inhibitors.PARP 抑制剂联合策略的最新进展。
Cancer Control. 2024 Jan-Dec;31:10732748241298329. doi: 10.1177/10732748241298329.
7
Targeting the DNA damage response in cancer.靶向癌症中的DNA损伤反应。
MedComm (2020). 2024 Oct 31;5(11):e788. doi: 10.1002/mco2.788. eCollection 2024 Nov.
8
Virtual screening, molecular dynamics simulations, and in vitro validation of EGFR inhibitors as breast cancer therapeutics.表皮生长因子受体（EGFR）抑制剂作为乳腺癌治疗药物的虚拟筛选、分子动力学模拟及体外验证
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9
Donafenib inhibits PARP1 expression and induces DNA damage, in combination with PARP1 inhibitors promotes apoptosis in liver cancer cells.多纳非尼抑制PARP1表达并诱导DNA损伤，与PARP1抑制剂联合使用可促进肝癌细胞凋亡。
Anticancer Drugs. 2024 Oct 1;35(9):789-805. doi: 10.1097/CAD.0000000000001631. Epub 2024 Jun 26.
10
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