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Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia
W.-H. Lin, S.-Y. Wu, T.-K. Yeh, C.-T. Chen, J.-S. Song, H.-Y. Shiao, C.-C. Kuo, T. Hsu, C.-T. Lu, P.-C. Wang, T.-S. Wu, Y.-H. Peng, H.-Y. Lin, C.-P. Chen, Y.-L. Weng, F.-C. Kung, M.-H. Wu, Y.-C. Su, K.-W. Huang, L.-H. Chou, C.-C. Hsueh, K.-J. Yen, P.-C. Kuo, C.-L. Huang, L.-T. Chen, C. Shih, H.-J. Tsai*, and W.-T. Jiaang*
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.