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Discovery of UMI-77 as a novel Ku70/80 inhibitor sensitizing cancer cells to DNA damaging agents in vitro and in vivo.
Chen, Xuening; Chen, Changkun; Luo, Chengmiao; Liu, Jianyong; Lin, Zhonghui.
Afiliación
  • Chen X; College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
  • Chen C; College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
  • Luo C; College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
  • Liu J; College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
  • Lin Z; College of Chemistry, Fuzhou University, Fuzhou, 350108, China. Electronic address: Zhonghui.lin@fzu.edu.cn.
Eur J Pharmacol ; 975: 176647, 2024 Jul 15.
Article en En | MEDLINE | ID: mdl-38754534
ABSTRACT
The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair capabilities of cancer cells. The Ku70/80 protein complex (Ku) plays a central role in double-strand breaks (DSBs) repair through the classical non-homologous end joining (c-NHEJ) pathway, and has proven to be one of the most promising drug target for cancer treatment when combined with radiotherapy or chemotherapy. In this study, we conducted a high-throughput screening of small-molecule inhibitors targeting the Ku complex by using a fluorescence polarization-based DNA binding assay. From a library of 11,745 small molecules, UMI-77 was identified as a potent Ku inhibitor, with an IC50 value of 2.3 µM. Surface plasmon resonance and molecular docking analyses revealed that UMI-77 directly bound the inner side of Ku ring, thereby disrupting Ku binding with DNA. In addition, UMI-77 also displayed potent inhibition against MUS81-EME1, a key player in homologous recombination (HR), demonstrating its potential for blocking both NHEJ- and HR-mediated DSB repair pathways. Further cell-based studies showed that UMI-77 could impair bleomycin-induced DNA damage repair, and significantly sensitized multiple cancer cell lines to the DNA-damaging agents. Finally, in a mouse xenograft tumor model, UMI-77 significantly enhanced the chemotherapeutic efficacy of etoposide with little adverse physiological effects. Our work offers a new avenue to combat chemoresistance in cancer treatment, and suggests that UMI-77 could be further developed as a promising candidate in cancer treatment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autoantígeno Ku / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Eur J Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autoantígeno Ku / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Eur J Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos