Structure-based design of new potent and highly selective PARP-1 inhibitor for treating colorectal cancer
Poly (ADP-ribose) polymerase 1 (PARP-1) exhibits high expression levels in colorectal cancer (CRC) patients and participates in multiple DNA damage repair pathways, thereby emerging as an attractive target. Herein, we identified a series of PARP-1 inhibitors (termed as compounds 1-6) by pharmacophore modelling, virtual screening and biological evaluation. Enzyme inhibition assays demonstrated that compound-5 significantly inhibited PARP-1 activity (IC<sub>50</sub> = 0.07 ± 0.01 nM) and exhibited high selectivity for PARP-1 among 63 different kinases. Molecular dynamic simulations indicated that compound-5 stably bound to the catalytic domain of PARP-1. Cellular assays demonstrated that compound-5 significantly inhibited the proliferation of a panel of human CRC cell lines (HCT116, SNU-1, Caco-2, HT-29). The data suggest that compound-5 may be a highly potent and selective PARP-1 inhibitor for CRC therapy.
Authors
- Chunying Jiang (ORCID: https://orcid.org/0000-0002-3505-9614)
- Miaomiao Niu (ORCID: https://orcid.org/0000-0001-6368-8525)
- Dongli Zhang (ORCID: https://orcid.org/0000-0002-0556-5532)
- Lin Du (ORCID: https://orcid.org/0000-0001-8751-4482)
- Yuting Wang (ORCID: https://orcid.org/0000-0002-7267-4026)
- Shudan Yang (ORCID: https://orcid.org/0000-0003-3825-2134)
Institutions
- China Pharmaceutical University (CN)
- Nantong University (CN)
- Soochow University (CN)
- Jilin Province Tumor Hospital (CN)
- Taizhou Fourth People's Hospital (CN)
- The Affiliated Taizhou People's Hospital of Nanjing Medical University (CN)
- Fourth People's Hospital of Changzhou (CN)
Publication Details
- Journal
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1080/14756366.2025.2542358
- Citations
- 2
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- National Natural Science Foundation of China