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Identification of a new inhibitor of KRAS-PDE delta interaction targeting KRAS mutant nonsmall cell lung cancer

文献类型：期刊论文

作者Leung, Elaine Lai-Han2,3; Luo, Lian Xiang2; Li, Ying2; Liu, Zhong-Qiu4; Li, Lan Lan1,5; Shi, Dan Feng1,5; Xie, Ying2; Huang, Min6; Lu, Lin Lin4; Duan, Fu Gang2
刊名INTERNATIONAL JOURNAL OF CANCER
出版日期2019-09-01
卷号145期号:5页码:1334-1345
ISSN号0020-7136
DOI10.1002/ijc.32222
通讯作者Yao, Xiao Jun(xjyao@must.edu.mo) ; Ward, David C.(biotin1@gmail.com) ; Liu, Liang(lliu@must.edu.mo)
英文摘要Oncogenic KRAS is considered a promising target for anti-cancer therapy. However, direct pharmacological strategies targeting KRAS-driven cancers remained unavailable. The prenyl-binding protein PDE delta, a transporter of KRAS, has been identified as a potential target for pharmacological inhibitor by selectively binding to its prenyl-binding pocket, impairing oncogenic KRAS signaling pathway. Here, we discovered a novel PDE delta inhibitor (E)-N '-((3-(tert-butyl)-2-hydroxy-6,7,8,9-tetrahydrodibenzo[b,dfuran-1-yl)methylene)-2,4-dihydroxybenzohydrazide(NHTD) by using a high-throughput docking-based virtual screening approach. In vitro and in vivo studies demonstrated that NHTD suppressed proliferation, induced apoptosis and inhibited oncogenic K-RAS signaling pathways by disrupting KRAS-PDE delta interaction in nonsmall cell lung cancer (NSCLC) harboring KRAS mutations. NHTD redistributed the localization of KRAS to endomembranes by targeting the prenyl-binding pocket of PDE delta and exhibited the suppression of abnormal KRAS function. Importantly, NHTD prevented tumor growth in xenograft and KRAS mutant mouse model, which presents an effective strategy targeting KRAS-driven cancer.
WOS关键词RAS ISOFORMS ; MUTATIONS ; TRANSPORT ; PROTEINS ; GAPS ; GEFS
资助项目Macao Science and Technology Development Fund[010/2016/A1] ; Macao Science and Technology Development Fund[046/2016/A2] ; Macao Science and Technology Development Fund[086/2015/A3]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000474668200017
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/289319]  
专题新药研究国家重点实验室
通讯作者Yao, Xiao Jun; Ward, David C.; Liu, Liang
作者单位1.Lanzhou Univ, Dept Chem, Lanzhou, Gansu, Peoples R China
2.Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau Inst Appl Res Med & Hlth, Ave Wai Long, Taipa, Macao, Peoples R China
3.Guangzhou Med Univ, Natl Clin Res Ctr Resp Dis, Dept Thorac Surg, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China
4.Guangzhou Univ Chinese Med, Int Inst Translat Chinese Med, Guangzhou, Guangdong, Peoples R China
5.Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou, Gansu, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Leung, Elaine Lai-Han,Luo, Lian Xiang,Li, Ying,et al. Identification of a new inhibitor of KRAS-PDE delta interaction targeting KRAS mutant nonsmall cell lung cancer[J]. INTERNATIONAL JOURNAL OF CANCER,2019,145(5):1334-1345.
APA Leung, Elaine Lai-Han.,Luo, Lian Xiang.,Li, Ying.,Liu, Zhong-Qiu.,Li, Lan Lan.,...&Liu, Liang.(2019).Identification of a new inhibitor of KRAS-PDE delta interaction targeting KRAS mutant nonsmall cell lung cancer.INTERNATIONAL JOURNAL OF CANCER,145(5),1334-1345.
MLA Leung, Elaine Lai-Han,et al."Identification of a new inhibitor of KRAS-PDE delta interaction targeting KRAS mutant nonsmall cell lung cancer".INTERNATIONAL JOURNAL OF CANCER 145.5(2019):1334-1345.

入库方式： OAI收割

来源：上海药物研究所

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