A small molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé COH29, un inhibiteur des ribonucléotides réductases
Ribonucleotide reductase (RNR) is an attractive target for anticancer agents given its central function in DNA synthesis, growth, metastasis and drug resistance of cancer cells. Current RNR inhibitors have shortcomings of short halflife, drug resistance and iron chelation. Here we report the development of a novel class of effective RNR inhibitors addressing these issues. A novel ligand-binding pocket on the RNR small subunit (RRM2) near the C-terminal tail was proposed by computer modeling and verified by site-directed mutagenesis and NMR techniques. A compound targeting this pocket was identified by virtual screening of the NCI diverse small molecule database. By lead optimization we developed the novel RNR inhibitor COH29 which acted as a potent inhibitor of recombinant and cellular human RNR enzymes. COH29 overcame hydroxyurea and gemcitabine resistance in cancer cells. It effectively inhibited proliferation of most cell lines in the NCI 60 human cancer panel, most notably ovarian cancer and leukemia, but exerted little effect on normal fibroblasts or endothelial cells. In mouse xenograft models of human cancer, COH29 treatment reduced tumor growth compared to vehicle. Site-directed mutagenesis, NMR and surface plasmon resonance biosensor studies confirmed COH29 binding to the proposed ligand-binding pocket, and offered evidence that for assembly blockade of the RRM1-RRM2 quaternary structure. Our findings offer preclinical validation of COH29 as a promising new class of RNR inhibitors with a new mechanism of inhibition, with broad potential for improved treatment of human cancer.