Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 12, Pages 3774-3783Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm900424a
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Funding
- Cancer Research U.K. Programme
- European Union FP6 Molecular Cancer Medicine Grant
- GI SPORE [IP50CA127003-02]
- Life Raft Group
- Daniel K. Ludwig Trust for Cancer Research
- Stutman GIST Cancer Research Fund
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Most of human gastrointestinal stromal tumors (GIST) are driven by activating mutations in the protooncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumor regrowth occurs as a result of them development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus, kinase resistance may be circumvented. A naphthalene diimide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilizes both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (similar to 1 mu M) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modeling studies with a telomeric quadruplex have been used to rationalize aspects of the experimental quadruplex melting data.
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