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Repositioning of Montelukast to inhibit proliferation of mutated KRAS pancreatic cancer through a novel mechanism that interfere the binding between KRAS and GTP/GDP.
Xia, Yannan; Zhang, Shujie; Luo, Hongyi; Wang, Yumeng; Jiang, Yuanyuan; Jiang, Jingwei; Yuan, Shengtao.
Afiliação
  • Xia Y; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, China.
  • Zhang S; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, China.
  • Luo H; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, China.
  • Wang Y; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, China.
  • Jiang Y; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, China.
  • Jiang J; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, China; Shuangyun BioMed Sci & Tech (Suzhou) Co., Ltd, China. Electronic address: jiangjingwei@126.com.
  • Yuan S; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, China. Electronic address: yuanst1967@163.com.
Eur J Pharmacol ; 961: 176157, 2023 Dec 15.
Article em En | MEDLINE | ID: mdl-37939992
Pancreatic cancer is one of the most lethal cancer types with 5-year survival rate of ∼10.8%. Various KRAS mutations exist in ∼85% pancreatic cancer cell lines. Mutated KRAS is a major cause that leads cancer cell proliferation. Chemotherapy is still the major treatment for pancreatic cancer. Alternatively, repositioning old drug to inhibit mutated KRAS may be a cost-effective way for pancreatic cancer treatment. In this study, we choose mutated KRAS (G12D) as a target. Based on mutated KRAS GTP binding domain (hydrolyze GTP to GDP), we perform virtual screening on FDA-approved drugs. Montelukast shows strong binding affinity to mutated KRAS as well as interfering both GTP and GDP binding to mutated KRAS. Furthermore, Montelukast shows very strong anti-proliferation effect on mutated KRAS pancreatic cancer cells both in vitro and in vivo. Our results support repositioning of Montelukast as single agent for pancreatic cancer treatment.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Proteínas Proto-Oncogênicas p21(ras) Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Proteínas Proto-Oncogênicas p21(ras) Idioma: En Ano de publicação: 2023 Tipo de documento: Article