1. Small-Molecule-Targeting Hairpin Loop of hTERT Promoter G-Quadruplex Induces Cancer Cell Death.
- Author
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Song JH, Kang HJ, Luevano LA, Gokhale V, Wu K, Pandey R, Sherry Chow HH, Hurley LH, and Kraft AS
- Subjects
- Animals, Apoptosis drug effects, Cell Death drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Humans, Male, Mice, Mice, SCID, Molecular Structure, Small Molecule Libraries chemistry, Structure-Activity Relationship, Telomerase metabolism, G-Quadruplexes drug effects, Small Molecule Libraries pharmacology, Telomerase antagonists & inhibitors
- Abstract
Increased telomerase activity is associated with malignancy and poor prognosis in human cancer, but the development of targeted agents has not yet provided clinical benefit. Here we report that, instead of targeting the telomerase enzyme directly, small molecules that bind to the G-hairpin of the hTERT G-quadruplex-forming sequence kill selectively malignant cells without altering the function of normal cells. RG260 targets the hTERT G-quadruplex stem-loop folding but not tetrad DNAs, leading to downregulation of hTERT expression. To improve physicochemical and pharmacokinetic properties, we derived a small-molecule analog, RG1603, from the parent compound. RG1603 induces mitochondrial defects including PGC1α and NRF2 inhibition and increases oxidative stress, followed by DNA damage and apoptosis. RG1603 injected as a single agent has tolerable toxicity while achieving strong anticancer efficacy in a tumor xenograft mouse model. These results demonstrate a unique approach to inhibiting the hTERT that functions by impairing mitochondrial activity, inducing cell death., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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