生物活性

• 靶点	Ribonucleotide Reductase IC50:8μM

• 描述The ribonucleotide reductase (RNR), the only enzyme responsible for the de novo conversion of ribonucleoside diphosphate (NDP) to deoxyribonucleoside diphosphate (dNDP), is the key regulator of intracellular dNTP (deoxyribonucleoside triphosphate) supply. RNR is an attractive target for anticancer agents given its central function in DNA synthesis, growth, metastasis, and drug resistance of cancer cells. Human RNR is composed of α subunits (RRM1) that contain the catalytic site and two binding sites for enzyme regulators, and β subunits (RRM2) with a binuclear iron co-factor that generates the stable tyrosyl radical necessary for catalysis. COH29 is a novel RNR inhibitor which acts as a potent inhibitor of both recombinant and cellular human RNR enzymes. COH29 inhibited recombinant RRM1/RRM2 activity in vitro with an IC₅₀ of 16 µM. COH29 interfered with RRM1-RRM2 binding in a dose-dependent manner. COH29 enhanced RRM1-RRM2 interaction at low dose (12.5 µM) but disrupted the complex at higher dose (> 25µM). In cultured KB human cancer cells, endogenously expressed RNR activity was approximately 50% decreased after 24 h incubation with 10 µM COH29. The IC₅₀ of COH29 is 8 µM in cell proliferation assays. Consistently, real-time KB cell growth was essentially halted by addition of 20 µM COH29 at 24 h. Impressive inhibition of most of the human cancer cell lines was observed in in vitro MTT cytotoxicity assays, with ovarian cancer and leukemia cells being the most sensitive to 10 µM COH29. In murine tumor xenograft models, COH29 resulted 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 was pronounced by Day 12 of treatment^[3].
• 作用机制COH29 docks at pocket 5 of hRRM2 with the extra phenyl ring touching Gly233 as predicted. Mutagenesis studies confirmed residues Asp271, Tyr323, Phe326, Val327, and Met350 are involved in COH29 binding^[3].