molecules of the month

Context. TAS1553 (Taiho Pharmaceutical) is an oral ribonucleotide reductase (RNR) inhibitor with antitumor activity. As the enzyme that catalyzes the rate-limiting step for deoxyribonucleotide triphosphate (dNTP) synthesis in cells, RNR has long been of interest to anticancer drug discovery efforts, especially since unlimited dNTP supply is key to one the most recognized hallmarks of cancer: uncontrolled proliferation. Currently, the 5 FDA-approved RNR inhibitors target either the large catalytic R1 subunit (gemcitabine, clofarabine, cladribine, fludarabine; all nucleoside analogs) or the small free radical-containing R2 subunit (hydroxyurea) of the protein, with these inhibitors showing negligible cross-reactivity between the subunits. The novel TAS1553 differentiates itself from these and other reported agents by targeting the R1-R2 protein-protein interaction (IC50 = 9.22 ± 1.40 µmol/L). Since the compound…