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

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.