Abstract
A series of indole analogs that are synthesized using the scaffold of a potent radiosensitizer, YTR107, were tested for their ability to alter the solubility of phosphorylated nucleophosmin 1 (pNPM1). NPM1 is critical for DNA double strand break (DSB) repair. In response to formation of DNA DSBs, phosphorylated T199 NPM1 binds to ubiquitinated chromatin, in a RNF8/RNF168-dependent manner, forming irradiation-induced foci (IRIF) that promote repair of DNA DSBs. A Western blot assay was developed using lead molecule, YTR107, for the purpose of screening newly synthesized molecules that target pNPM1 in irradiated cells. A colony formation assay was used to demonstrate the radiosensitization properties of the compounds. Compounds that enhanced the extractability of pNPM1 upon radiation treatment possessed radiosensitization properties.
Keywords:
Assay development; Cancer; DNA repair; Indole analogs; Lung cancer; NPM1; Nucleophosmin 1; PNR605; Radiation; Radiosensitizers; YTR107.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Validation Study
MeSH terms
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Barbiturates / pharmacology*
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Blotting, Western / methods*
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Cell Line
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Cell Line, Tumor
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Cell Nucleus / chemistry
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Cell Nucleus / metabolism
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Cell Nucleus / radiation effects
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Centrosome / chemistry
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Centrosome / metabolism
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Centrosome / radiation effects
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Chromatin / chemistry
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Chromatin / metabolism
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Chromatin / radiation effects
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DNA Breaks, Double-Stranded / radiation effects*
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Fibroblasts / radiation effects
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Gamma Rays
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Humans
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Indoles / pharmacology*
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Nuclear Proteins / genetics
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Nuclear Proteins / isolation & purification*
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Nuclear Proteins / metabolism
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Nucleophosmin
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Phosphorylation
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Radiation-Sensitizing Agents / pharmacology*
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Tumor Stem Cell Assay
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Ubiquitin / genetics
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Ubiquitin / metabolism
Substances
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5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)trione
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Barbiturates
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Chromatin
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Indoles
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NPM1 protein, human
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Nuclear Proteins
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Radiation-Sensitizing Agents
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Ubiquitin
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Nucleophosmin