Open AccessA ribonucleotide reductase inhibitor with deoxyribonucleoside‐reversible cytotoxicity
Author(s) -
Crona Mikael,
Codó Paula,
Jonna Venkateswara Rao,
Hofer Anders,
Fernandes Aristi P.,
Tholander Fredrik
Publication year - 2016
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2016.07.008
Subject(s) - ribonucleotide reductase , enzyme , biochemistry , deoxyribonucleotides , ribonucleotide , biology , chemistry , enzyme inhibitor , cell cycle , protein subunit , cytotoxicity , cell , in vitro , nucleotide , gene
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.