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Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia.
Lin, Wen-Hsing; Wu, Su-Ying; Yeh, Teng-Kuang; Chen, Chiung-Tong; Song, Jen-Shin; Shiao, Hui-Yi; Kuo, Ching-Chuan; Hsu, Tsu; Lu, Cheng-Tai; Wang, Pei-Chen; Wu, Tsung-Sheng; Peng, Yi-Hui; Lin, Hui-You; Chen, Ching-Ping; Weng, Ya-Ling; Kung, Fang-Chun; Wu, Mine-Hsine; Su, Yu-Chieh; Huang, Kuo-Wei; Chou, Ling-Hui; Hsueh, Ching-Cheng; Yen, Kuei-Jung; Kuo, Po-Chu; Huang, Chen-Lung; Chen, Li-Tzong; Shih, Chuan; Tsai, Hui-Jen; Jiaang, Weir-Torn.
Afiliação
  • 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.
J Med Chem ; 62(24): 11135-11150, 2019 12 26.
Article em En | MEDLINE | ID: mdl-31721578
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Leucemia Mieloide Aguda / Proteínas Proto-Oncogênicas c-kit / Tumores do Estroma Gastrointestinal / Inibidores de Proteínas Quinases / Tirosina Quinase 3 Semelhante a fms / Mutação / Antineoplásicos Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Leucemia Mieloide Aguda / Proteínas Proto-Oncogênicas c-kit / Tumores do Estroma Gastrointestinal / Inibidores de Proteínas Quinases / Tirosina Quinase 3 Semelhante a fms / Mutação / Antineoplásicos Idioma: En Ano de publicação: 2019 Tipo de documento: Article