title: A ribonucleotide reductase inhibitor with deoxyribonucleoside-reversible cytotoxicity.
abstract: Ribonucleotide Reductase (RNR) is the sole enzyme that catalyzes the reduction of ribonucleotides into deoxyribonucleotides. Even though RNR is a recognized target for antiproliferative molecules, and the main target of the approved drug hydroxyurea, few new leads targeted to this enzyme have been developed. We have evaluated a recently identified set of RNR inhibitors with respect to inhibition of the human enzyme and cellular toxicity. One compound, NSC73735, is particularly interesting; it is specific for leukemia cells and is the first identified compound that hinders oligomerization of the mammalian large RNR subunit. Similar to hydroxyurea, it caused a disruption of the cell cycle distribution of cultured HL-60 cells. In contrast to hydroxyurea, the disruption was reversible, indicating higher specificity. NSC73735 thus defines a potential lead candidate for RNR-targeted anticancer drugs, as well as a chemical probe with better selectivity for RNR inhibition than hydroxyurea.
authors: Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors: Mikael
authors: M
authors: Crona
authors: Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors: Paula
authors: P
authors: Codó
authors: Department of Medical Biochemistry and Biophysics, Umeå University, 90187, Umeå, Sweden.
authors: Venkateswara Rao
authors: VR
authors: Jonna
authors: Department of Medical Biochemistry and Biophysics, Umeå University, 90187, Umeå, Sweden.
authors: Anders
authors: A
authors: Hofer
authors: Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors: Aristi P
authors: AP
authors: Fernandes
authors: Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden. Electronic address: fredrik.tholander@ki.se.
authors: Fredrik
authors: F
authors: Tholander
mesh_terms: D001681:Biological Assay; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003853:Deoxyribonucleosides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013696:Temperature
chemical_list: D003853:Deoxyribonucleosides; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D012264:Ribonucleotide Reductases; D006918:Hydroxyurea
keywords: Antiproliferative compounds; Cell cycle; Cytotoxicity; GEMMA; Inhibitors; Nucleotide metabolism; Oligomeric state; Ribonucleotide reductase