COH-29

A small-molecule inhibitor of ribonucleotide reductase (RNR) that binds to RRM2, interfering with RRM1-RRM2 interactions with IC50 of 16 uM; overcomes hydroxyurea and gemcitabine resistance in cancer cells, effectively inhibits proliferation of most cell lines in the NCI 60 human cancer panel; inhibits nonhomologous end joining (NHEJ) efficiency in HCC1937 cells; reduced tumor growth in mouse xenograft models of human cancer. (In Vitro) :COH29 (RNR Inhibitor COH29) overcome hydroxyurea and gemcitabine resistance in cancer cells. It effectively inhibits proliferation of most cell lines in the NCI 60 human cancer panel, most notably ovarian cancer and leukemia, but exerts little effect on normal fibroblasts or endothelial cells. Site-directed mutagenesis, NMR and surface plasmon resonance biosensor studies confirm COH29 binding to the proposed ligand-binding pocket and offer evidence for assembly blockade of the RRM1-RRM2 quaternary structure. (In Vivo) :COH29 results in a dose-dependent inhibition of MOLT-4 tumor xenograft growth with twice-daily oral dosing at 50 mg/kg and 100 mg/kg, which is pronounced by Day 12 of treatment. Similarly, 7 days of treatment of mice bearing TOV11D xenografts with 200, 300, or 400 mg/kg/day COH29 results in a dose-dependent inhibition of tumor xenograft growth. Tumor growth is significantly inhibited compared with the control group.