2. Academic Validation
  3. Development and validation of a novel assay to identify radiosensitizers that target nucleophosmin 1

Development and validation of a novel assay to identify radiosensitizers that target nucleophosmin 1

  • Bioorg Med Chem. 2015 Jul 1;23(13):3681-6. doi: 10.1016/j.bmc.2015.04.018.
Narsimha R Penthala 1,  Peter A Crooks 1,  Michael L Freeman 2,  Konjeti R Sekhar 3
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
  • 2 Department of Radiation Oncology, Vanderbilt University School Medicine, Nashville, TN 37232, USA.
  • 3 Department of Radiation Oncology, Vanderbilt University School Medicine, Nashville, TN 37232, USA. Electronic address: raja.konjeti@vanderbilt.edu.
PMID: 25922180 DOI: 10.1016/j.bmc.2015.04.018
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.

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