title: DDRI-9: a novel DNA damage response inhibitor that blocks mitotic progression.
abstract: The DNA damage response (DDR) is an emerging target for cancer therapy. By modulating the DDR, including DNA repair and cell cycle arrest, the efficacy of anticancer drugs can be enhanced and side effects reduced. We previously screened a chemical library and identified novel DDR inhibitors including DNA damage response inhibitor-9 (DDRI-9; 1H-Purine-2,6-dione,7-[(4-fluorophenyl)methyl]-3,7-dihydro-3-methyl-8-nitro). In this study, we characterized DDRI-9 activity and found that it inhibited phosphorylated histone variant H2AX foci formation upon DNA damage, delayed DNA repair, and enhanced the cytotoxicity of etoposide and ionizing radiation. It also reduced the foci formation of DNA repair-related proteins, including the protein kinase ataxia-telangiectasia mutated, DNA-dependent protein kinase, breast cancer type 1 susceptibility protein, and p53-binding protein 1, but excluding mediator of DNA damage checkpoint protein 1. Cell cycle analysis revealed that DDRI-9 blocked mitotic progression. Like other mitotic inhibitors, DDRI-9 treatment resulted in the accumulation of mitotic protein and induced cell death. Thus, DDRI-9 may affect both DDR signal amplification and mitotic progression. This study suggests that DDRI-9 is a good lead molecule for the development of anticancer drugs.
authors: New Experimental Therapeutics Branch, Division of Convergence Technology, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Dong Wha
authors: DW
authors: Jun
authors: New Experimental Therapeutics Branch, Division of Convergence Technology, National Cancer Center, Goyang, Gyeonggi, Korea.|System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Mihwa
authors: M
authors: Hwang
authors: Molecular Imaging and Therapy Branch, Division of Convergence Technology, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Yun-Hee
authors: YH
authors: Kim
authors: Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Kyung-Tae
authors: KT
authors: Kim
authors: New Experimental Therapeutics Branch, Division of Convergence Technology, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Sunshin
authors: S
authors: Kim
authors: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Chang-Hun
authors: CH
authors: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D045325:HCT116 Cells; D006367:HeLa Cells; D006657:Histones / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D008938:Mitosis / Q000187:drug effects* / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D011687:Purines; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA damage response; DNA repair-related proteins; anticancer drugs; mitotic inhibitors; γH2AX