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
  • 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: [email protected].
  • 6. School of Pharmacy, North China University of Science and Technology, Tangshan 063210, China. Electronic address: [email protected].
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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