The identification of novel 5'-amino gemcitabine analogs as potent RRM1 inhibitors.

Autor: Labroli MA; Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: marc.labroli@merck.com., Dwyer MP; Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA., Shen R; Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-3, Boston, MA 02115, USA., Popovici-Muller J; Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-3, Boston, MA 02115, USA., Pu Q; Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-3, Boston, MA 02115, USA., Wyss D; Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., McCoy M; Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Barrett D; Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Davis N; Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA., Seghezzi W; Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA., Shanahan F; Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA., Taricani L; Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA., Beaumont M; Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA., Malinao MC; Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA., Parry D; Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA., Guzi TJ; Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-3, Boston, MA 02115, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2014 Apr 01; Vol. 22 (7), pp. 2303-10. Date of Electronic Publication: 2014 Feb 15.
DOI: 10.1016/j.bmc.2014.02.007
Abstrakt: 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.)
Databáze: MEDLINE
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