國家衛生研究院 NHRI:Item 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:	[Weir-Torn Jiaang] Periodical Articles [Chuan Shih(2014-2017)] Periodical Articles [Ching-Chuan Kuo] Periodical Articles [Chiung-Tong Chen] Periodical Articles [Teng-Kuang Yeh] Periodical Articles [Su-Ying Wu] Periodical Articles [Hui-Jen Tsai] Periodical Articles [Li-Tzong Chen] Periodical Articles

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