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

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

  • Adv Sci (Weinh). 2025 Jun 16:e01916. doi: 10.1002/advs.202501916.
Yuan Gao 1 2,  Jiawei Zhou 2 3,  Chen-Chen Wang 4,  Zong-Hao Wang 2 3,  Nian-Dong Mao 2 4,  Meng-Lan He 2 3,  Peng-Peng Zhang 2 3,  Ping Huang 5,  Guo-Wei Ye 2 3,  Yu-Qing Zhang 2 3,  Feng-Hui Tang 2 3,  Hang Zhang 6,  Tian Xie 1 2 3,  Xiang-Yang Ye 2 3
Affiliations

Affiliations

  • 1 Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang Province, 310000, China.
  • 2 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310000, China.
  • 3 Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310000, China.
  • 4 College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310000, China.
  • 5 Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People' s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang Province, 310000, China.
  • 6 School of Basic Medical Science, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310000, China.
PMID: 40521858 DOI: 10.1002/advs.202501916
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 (IC50: 17.3 nM) and PARP1 (IC50: 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.

Keywords

ATR; Anticancer; Dual Inhibitor; PARP1; TNBC.

Figures
Products