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

  • J Med Chem. 2019 Dec 26;62(24):11135-11150. doi: 10.1021/acs.jmedchem.9b01229.
Wen-Hsing Lin  1 ,  Su-Ying Wu  1 ,  Teng-Kuang Yeh  1 ,  Chiung-Tong Chen  1 ,  Jen-Shin Song  1 ,  Hui-Yi Shiao  1 ,  Ching-Chuan Kuo  1 ,  Tsu Hsu  1 ,  Cheng-Tai Lu  1 ,  Pei-Chen Wang  1 ,  Tsung-Sheng Wu  1 ,  Yi-Hui Peng  1 ,  Hui-You Lin  2 ,  Ching-Ping Chen  1 ,  Ya-Ling Weng  1 ,  Fang-Chun Kung  1 ,  Mine-Hsine Wu  1 ,  Yu-Chieh Su  1 ,  Kuo-Wei Huang  2 ,  Ling-Hui Chou  1 ,  Ching-Cheng Hsueh  1 ,  Kuei-Jung Yen  1 ,  Po-Chu Kuo  1 ,  Chen-Lung Huang  1 ,  Li-Tzong Chen  2 ,  Chuan Shih  1 ,  Hui-Jen Tsai  2 ,  Weir-Torn Jiaang  1
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C.
  • 2. National Institute of Cancer Research , National Health Research Institutes , Tainan City 704 , Taiwan R.O.C.
PMID: 31721578 DOI: 10.1021/acs.jmedchem.9b01229
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.