A ribonucleotide reductase inhibitor with deoxyribonucleoside-reversible cytotoxicity

作者：Crona Mikael; Codo Paula; Jonna Venkateswara Rao; Hofer Anders; Fernandes Aristi P; Tholander Fredrik^*

来源：Molecular Oncology, 2016, 10(9): 1375-1386.

DOI：10.1016/j.molonc.2016.07.008

• Ribonucleotide reductase
• Nucleotide metabolism
• Inhibitors
• Antiproliferative compounds
• Cell cycle
• Cytotoxicity
• Oligomeric state
• GEMMA

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.

• 出版日期2016-11