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http://ir.nhri.org.tw/handle/3990099045/12442
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| Title: | Identification of a multitargeted tyrosine kinase inhibitor for the treatment of gastrointestinal stromal tumors and acute myeloid leukemia |
| Authors: | Lin, WH;Wu, SY;Yeh, TK;Chen, CT;Song, JS;Shiao, HY;Kuo, CC;Hsu, T;Lu, CT;Wang, PC;Wu, TS;Peng, YH;Lin, HY;Chen, CP;Weng, YL;Kung, FC;Wu, MH;Su, YC;Huang, KW;Chou, LH;Hsueh, CC;Yen, KJ;Kuo, PC;Huang, CL;Chen, LT;Shih, C;Tsai, HJ;Jiaang, WT |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research;National Institute of Cancer Research |
| Abstract: | 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. |
| Date: | 2019-12 |
| Relation: | Journal of Medicinal Chemistry. 2019 Dec;62(24):11135-11150. |
| Link to: | http://dx.doi.org/10.1021/acs.jmedchem.9b01229 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000505633400013 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85076911703 |
| Appears in Collections: | [蔣維棠] 期刊論文
[石全(2014-2017)] 期刊論文
[郭靜娟] 期刊論文
[陳炯東] 期刊論文
[葉燈光] 期刊論文
[伍素瑩] 期刊論文
[蔡慧珍] 期刊論文
[陳立宗] 期刊論文
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| ISI000505633400013.pdf | | 5319Kb | Adobe PDF | 384 | View/Open |
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