Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia
| Autor: | Hui-You Lin, Yi-Hui Peng, Kuo Wei Huang, Chen-Lung Huang, Mine-Hsine Wu, Chuan Shih, Teng-Kuang Yeh, Weir-Torn Jiaang, Ching-Chuan Kuo, Tsu Hsu, Ching-Ping Chen, Ya-Ling Weng, Chiung-Tong Chen, Fang-Chun Kung, Wen-Hsing Lin, Hui Yi Shiao, Jen-Shin Song, Ling-Hui Chou, Tsung-Sheng Wu, Kuei-Jung Yen, Pei-Chen Wang, Ching-Cheng Hsueh, Yu-Chieh Su, Cheng-Tai Lu, Hui-Jen Tsai, Su-Ying Wu, Li-Tzong Chen, Po-Chu Kuo |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Stromal cell Gastrointestinal Stromal Tumors medicine.drug_class Mice Nude Antineoplastic Agents Apoptosis Stem cell factor Mice SCID Tyrosine-kinase inhibitor Receptor tyrosine kinase Rats Sprague-Dawley Mice Mice Inbred NOD hemic and lymphatic diseases Drug Discovery Tumor Cells Cultured medicine Animals Humans Phosphorylation Kinase activity Protein Kinase Inhibitors neoplasms Cell Proliferation Gastrointestinal Neoplasms Mice Inbred ICR biology Chemistry Kinase Cell growth Myeloid leukemia Xenograft Model Antitumor Assays digestive system diseases Leukemia Myeloid Acute Proto-Oncogene Proteins c-kit Pyrimidines fms-Like Tyrosine Kinase 3 Mutation biology.protein Cancer research Molecular Medicine Female |
| Zdroj: | Journal of Medicinal Chemistry. 62:11135-11150 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a, with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML. |
| Databáze: | OpenAIRE |
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