2. Academic Validation
  3. Design, synthesis, and biological evaluation of hydrophobic-tagged poly (ADP-ribose) polymerase 1 (PARP1) degraders

Design, synthesis, and biological evaluation of hydrophobic-tagged poly (ADP-ribose) polymerase 1 (PARP1) degraders

  • Bioorg Chem. 2026 Mar:170:109507. doi: 10.1016/j.bioorg.2026.109507.
Jiaqian Li 1,  Yang Cui 2,  Mengyu Xiong 3,  Liying Zhang 1,  Shuo Mu 1,  Ziqi He 1,  Hongcheng Zhu 4,  Kaiyin Yang 5,  Qidi Zhong 6
Affiliations

Affiliations

  • 1 School of Pharmacy, North China University of Science and Technology, Tangshan 063210, China.
  • 2 Pharmaceutical Department, Handan Central Hospital, Handan 056001, China.
  • 3 School of Public health, North China University of Science and Technology, Tangshan 063210, China.
  • 4 North China University of Science and Technology Affiliated Hospital, TangShan 063000, China.
  • 5 School of Pharmacy, North China University of Science and Technology, Tangshan 063210, China. Electronic address: 1272581188@qq.com.
  • 6 School of Pharmacy, North China University of Science and Technology, Tangshan 063210, China. Electronic address: qidizhong@ncst.edu.cn.
PMID: 41564696 DOI: 10.1016/j.bioorg.2026.109507
Abstract

Given its critical role in mediating the DNA damage response and repair, Poly (ADP-ribose) polymerase-1 (PARP1) has been established as a significant therapeutic target for Cancer and a multitude of Other human diseases. In this study, a novel series of hydrophobic tagging (HyT) derivatives were developed through design, synthesis, and evaluation to induce the degradation of PARP1. Leading compound 11e demonstrated significant efficacy in the triple-negative breast Cancer cell line MDA-MB-231, potently degrading PARP1 in a concentration- and time-dependent manner, thereby effectively inhibiting Cancer cell proliferation and migration. Moreover, a degradation of PARP1 was induced by 11e in various BRCA1/2-proficient carcinoma-derived lines, with potency observed at low compound levels. In conclusion, compound 11e, a novel and highly effective PARP1 degrading agent, displays superior degradation capability and holds considerable promise for future clinical applications.

Keywords

Cancer; Degradation; Hydrophobic tagging; PARP1.

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