Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia.Lin, W.H., Wu, S.Y., Yeh, T.K., Chen, C.T., Song, J.S., Shiao, H.Y., Kuo, C.C., Hsu, T., Lu, C.T., Wang, P.C., Wu, T.S., Peng, Y.H., Lin, H.Y., Chen, C.P., Weng, Y.L., Kung, F.C., Wu, M.H., Su, Y.C., Huang, K.W., Chou, L.H., Hsueh, C.C., Yen, K.J., Kuo, P.C., Huang, C.L., Chen, L.T., Shih, C., Tsai, H.J., Jiaang, W.T.
(2019) J Med Chem 62: 11135-11150
- PubMed: 31721578
- DOI: 10.1021/acs.jmedchem.9b01229
- Structures With Same Primary Citation
- PubMed 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 ...
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.
Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , No. 35, Keyan Road , Zhunan Town, Miaoli County 350 , Taiwan R.O.C.