A ribonucleotide reductase inhibitor with deoxyribonucleoside-reversible cytotoxicity.

Crona M, Codó P, Jonna VR, Hofer A, Fernandes AP, Tholander F

Mol Oncol 10 (9) 1375-1386 [2016-11-00; online 2016-07-26]

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.

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PubMed 27511871

DOI 10.1016/j.molonc.2016.07.008

Crossref 10.1016/j.molonc.2016.07.008

S1574-7891(16)30068-0