2. Academic Validation
  3. Design and synthesis of the first PARP-1 and proteasome dual inhibitors to treat breast cancer

Design and synthesis of the first PARP-1 and proteasome dual inhibitors to treat breast cancer

  • Eur J Med Chem. 2024 Jan 15:264:115943. doi: 10.1016/j.ejmech.2023.115943.
Hualong He 1,  Wan Yang 1,  Yaojie Shi 1,  Xin Chen 2,  Xinyi Chen 1,  Xiang Hu 1,  Xinyue Li 1,  Yingyue Yang 2,  Zhihao Liu 1,  Tinghong Ye 1,  Ningyu Wang 3,  Luoting Yu 4
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
  • 3 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China. Electronic address: wangny-swjtu@swjtu.edu.cn.
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yuluot@scu.edu.cn.
PMID: 38039793 DOI: 10.1016/j.ejmech.2023.115943
Abstract

PARP-1 is a crucial factor in repairing DNA single strand damage and maintaining genomic stability. However, the use of PARP-1 inhibitors is limited to combination with chemotherapy or radiotherapy, or as a single agent for indications carrying HRR defects. The ubiquitin-proteasome system processes the majority of cellular proteins and is the principal manner by which cells regulate protein homeostasis. Proteasome inhibitors can cooperate with PARP-1 inhibitors to inhibit DNA homologous recombination repair function. In this study, we designed and synthesized the first dual PARP-1 and Proteasome Inhibitor based on Olaparib and Ixazomib. Both compounds 42d and 42i exhibited excellent proliferation inhibition and dual-target synergistic effects on cells that were insensitive to PARP-1 inhibitors. Further mechanistic evaluations revealed that 42d and 42i could inhibit homologous recombination repair function by down-regulating the expression of BRCA1 and RAD51. Additionally, 42i induced more significant Apoptosis and showed better inhibitory effect on cell proliferation in clonal formation experiments in breast Cancer cells than 42d. In summary, our study presented a new class of dual PARP-1/Proteasome inhibitors with significant synergistic effects for the treatment of breast Cancer.

Keywords

Cancer therapy; DNA damage; Dual inhibitors; PARP-1; Proteasome.

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