1. The identification of novel 5'-amino gemcitabine analogs as potent RRM1 inhibitors.
- Author
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Labroli MA, Dwyer MP, Shen R, Popovici-Muller J, Pu Q, Wyss D, McCoy M, Barrett D, Davis N, Seghezzi W, Shanahan F, Taricani L, Beaumont M, Malinao MC, Parry D, and Guzi TJ
- Subjects
- Cell Line, Tumor, Deoxycytidine chemistry, Deoxycytidine pharmacology, Dose-Response Relationship, Drug, High-Throughput Screening Assays, Humans, Magnetic Resonance Spectroscopy, Molecular Structure, Ribonucleoside Diphosphate Reductase, Structure-Activity Relationship, Gemcitabine, Deoxycytidine analogs & derivatives, Tumor Suppressor Proteins antagonists & inhibitors
- Abstract
The ribonucleotide reductase (RNR) enzyme is a heteromer of RRM1 and RRM2 subunits. The active enzyme catalyzes de novo reduction of ribonucleotides to generate deoxyribonucleotides (dNTPs), which are required for DNA replication and DNA repair processes. Complexity in the generation of physiologically relevant, active RRM1/RRM2 heterodimers was perceived as limiting to the identification of selective RRM1 inhibitors by high-throughput screening of compound libraries and led us to seek alternative methods to identify lead series. In short, we found that gemcitabine, as its diphosphate metabolite, represents one of the few described active site inhibitors of RRM1. We herein describe the identification of novel 5'-amino gemcitabine analogs as potent RRM1 inhibitors through in-cell phenotypic screening., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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