Identification of a new inhibitor of KRAS‐PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer
| Autor: | David C. Ward, Fu Gang Duan, Ying Xie, Zhongqiu Liu, Liang Liu, Elaine Lai-Han Leung, Dan Feng Shi, Jian Ding, Xiao Jun Yao, Lan Lan Li, Lin Lin Lu, Min Huang, Xing Xing Fan, Lian Xiang Luo, Zhong Wen Yuan, Ying Li, Ju-Min Huang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Cancer Research Lung Neoplasms endocrine system diseases Mutant Mice Nude medicine.disease_cause Proto-Oncogene Proteins p21(ras) Rats Sprague-Dawley Mice Random Allocation 03 medical and health sciences 0302 clinical medicine In vivo Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Animals Humans neoplasms Benzofurans Cyclic Nucleotide Phosphodiesterases Type 6 Chemistry Hydrazones Transporter Xenograft Model Antitumor Assays digestive system diseases In vitro Rats respiratory tract diseases Oncology A549 Cells Apoptosis Docking (molecular) 030220 oncology & carcinogenesis NIH 3T3 Cells Cancer research Female KRAS Signal transduction |
| Zdroj: | International Journal of Cancer. 145:1334-1345 |
| ISSN: | 1097-0215 0020-7136 |
| DOI: | 10.1002/ijc.32222 |
| Popis: | 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 PDEδ, 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 PDEδ 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-PDEδ 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 PDEδ 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. |
| Databáze: | OpenAIRE |
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