Discovery of naphthacemycins as a novel class of PARP1 inhibitors

  • Bioorg Med Chem Lett. 2019 Aug 1;29(15):1904-1908. doi: 10.1016/j.bmcl.2019.05.055.
Wenbin Shen  1 ,  Xinhua Lu  2 ,  Jingtong Zhu  1 ,  Yunlong Mu  3 ,  Yan Xu  4 ,  Jian Gao  5 ,  Xuexia Zhang  6 ,  Zhihui Zheng  7
Affiliations
  • 1. New Drug Research & Development Center, North China Pharmaceutical Group Corporation, Shijiazhuang 050015, Hebei, China; Key Laboratory for New Drug Screening Technology of Shijiazhuang City, Shijiazhuang 050015, Hebei, China.
  • 2. New Drug Research & Development Center, North China Pharmaceutical Group Corporation, Shijiazhuang 050015, Hebei, China; National Microbial Medicine Engineering & Research Center, Shijiazhuang 050015, Hebei, China; Key Laboratory for New Drug Screening Technology of Shijiazhuang City, Shijiazhuang 050015, Hebei, China.
  • 3. National Microbial Medicine Engineering & Research Center, Shijiazhuang 050015, Hebei, China; Hebei Industry Microbial Metabolic Engineering & Technology Research Center, Shijiazhuang 050015, Hebei, China.
  • 4. New Drug Research & Development Center, North China Pharmaceutical Group Corporation, Shijiazhuang 050015, Hebei, China; Hebei Industry Microbial Metabolic Engineering & Technology Research Center, Shijiazhuang 050015, Hebei, China.
  • 5. New Drug Research & Development Center, North China Pharmaceutical Group Corporation, Shijiazhuang 050015, Hebei, China; National Microbial Medicine Engineering & Research Center, Shijiazhuang 050015, Hebei, China.
  • 6. New Drug Research & Development Center, North China Pharmaceutical Group Corporation, Shijiazhuang 050015, Hebei, China; National Microbial Medicine Engineering & Research Center, Shijiazhuang 050015, Hebei, China; Hebei Industry Microbial Metabolic Engineering & Technology Research Center, Shijiazhuang 050015, Hebei, China. Electronic address: [email protected].
  • 7. New Drug Research & Development Center, North China Pharmaceutical Group Corporation, Shijiazhuang 050015, Hebei, China; National Microbial Medicine Engineering & Research Center, Shijiazhuang 050015, Hebei, China; Key Laboratory for New Drug Screening Technology of Shijiazhuang City, Shijiazhuang 050015, Hebei, China. Electronic address: [email protected].
PMID: 31153806 DOI: 10.1016/j.bmcl.2019.05.055
Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein that plays important roles in a variety of nuclear processes, and it has been proved a prominent target in oncology for its key function in DNA damage repair. In this study, we discovered a series of naphthacemycins as a new class of PARP1 inhibitors from a microbial metabolites library via high-throughput screening. Compound I, one of this series of compounds, could reduce cellular poly (ADP-ribose) level, trap PARP1 on the damaged DNA and elevate the level of γ-H2AX, and showed the selective cytotoxicity against BRCA1-deficient cell line. Our study provided a potential scaffold for the development of new PARP1 inhibitors in Cancer therapy.

Keywords
High-throughput screening; Microbial metabolites; Molecular docking; Naphthacemycins; PARP1 inhibitor.