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

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

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.

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