title: The identification of novel 5'-amino gemcitabine analogs as potent RRM1 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.
authors.affiliation: Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: marc.labroli@merck.com.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Labroli
authors.affiliation: Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dwyer
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-3, Boston, MA 02115, USA.
authors.forename: Ruichao
authors.initials: R
authors.lastname: Shen
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-3, Boston, MA 02115, USA.
authors.forename: Janeta
authors.initials: J
authors.lastname: Popovici-Muller
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-3, Boston, MA 02115, USA.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Pu
authors.affiliation: Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wyss
authors.affiliation: Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: McCoy
authors.affiliation: Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Dianah
authors.initials: D
authors.lastname: Barrett
authors.affiliation: Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Davis
authors.affiliation: Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seghezzi
authors.affiliation: Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Shanahan
authors.affiliation: Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: Taricani
authors.affiliation: Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Maribel
authors.initials: M
authors.lastname: Beaumont
authors.affiliation: Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Malinao
authors.affiliation: Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, USA.
authors.forename: David
authors.initials: D
authors.lastname: Parry
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-3, Boston, MA 02115, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Guzi
mesh_terms: D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012262:Ribonucleoside Diphosphate Reductase; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
chemical_list: D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine
keywords: CHK1; Deoxyribonucleotides; Gemcitabine; Oncology; Ribonucleotide reductase