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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis
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Cell Proliferation
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Female
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Gastrointestinal Neoplasms / drug therapy
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Gastrointestinal Neoplasms / enzymology
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Gastrointestinal Neoplasms / genetics
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Gastrointestinal Neoplasms / pathology
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Gastrointestinal Stromal Tumors / drug therapy*
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Gastrointestinal Stromal Tumors / enzymology
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Gastrointestinal Stromal Tumors / genetics
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Gastrointestinal Stromal Tumors / pathology
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / enzymology
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / pathology
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Male
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Mice
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Mice, Inbred ICR
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Mutation*
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Phosphorylation
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
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Proto-Oncogene Proteins c-kit / genetics
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Rats, Sprague-Dawley
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
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fms-Like Tyrosine Kinase 3 / genetics
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrimidines
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FLT3 protein, human
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KIT protein, human
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Proto-Oncogene Proteins c-kit
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fms-Like Tyrosine Kinase 3