Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia.

Autor:	Lin WH; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Wu SY; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Yeh TK; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Chen CT; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Song JS; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Shiao HY; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Kuo CC; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Hsu T; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Lu CT; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Wang PC; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Wu TS; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Peng YH; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Lin HY; National Institute of Cancer Research , National Health Research Institutes , Tainan City 704 , Taiwan R.O.C., Chen CP; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Weng YL; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Kung FC; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Wu MH; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Su YC; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Huang KW; National Institute of Cancer Research , National Health Research Institutes , Tainan City 704 , Taiwan R.O.C., Chou LH; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Hsueh CC; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Yen KJ; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Kuo PC; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Huang CL; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Chen LT; National Institute of Cancer Research , National Health Research Institutes , Tainan City 704 , Taiwan R.O.C., Shih C; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C., Tsai HJ; National Institute of Cancer Research , National Health Research Institutes , Tainan City 704 , Taiwan R.O.C., Jiaang WT; Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2019 Dec 26; Vol. 62 (24), pp. 11135-11150. Date of Electronic Publication: 2019 Dec 06.
DOI:	10.1021/acs.jmedchem.9b01229
Abstrakt:	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:	MEDLINE
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