Abstract 3258: Development of novel ribonucleotide reductase inhibitors: A story from structural analysis to preclinical study

Abstract

Abstract The goal of this project is to develop new class inhibitors for Ribonucleotide Reductase (RR), a key enzyme for DNA synthesis. These inhibitors are more effective than existing small molecule therapies, and can overcome resistance from Hydroxyurea (HU), the only FDA approved drug for targeting RR-based cancers. In addition, this new class of inhibitors will ameliorate the severe iron chelating side effects associated with 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, Triapine®), a compound that is currently been testing in human phase II clinic trials. A lead compound, COH29 (US Patent No. 54435.8056.US01) with sub-micro molar range inhibition was developed through modification of a hit identified from screening a diverse compound library from NCI Developmental Therapeutics Program (DTP). COH29 demonstrated 90.2% inhibitory activity of recombinant human RRM2/RRM1 enzyme complex at 9 µM in vitro. Moreover, examine the cytotoxicity of COH29 in a NCI broad panel of 60 human cancer cell lines in vitro by 5 doses MTT cytotoxicity assay indicated COH29 show a good inhibition against cancer cells special to leukemia and ovarian cancer cells. Importantly, COH29 shows less toxicity to human normal fibroblast cells as compared to 3-AP. Results from computer modeling and biophysical measurements suggest that COH29 interferes with the radical transfer pathway at the interface between RRM1 and RRM2. This represents a unique binding mechanism that is completely different from existing known inhibitors. Biacore binding analysis, computer docking, as well as NMR Saturation Transfer Difference (STD) studies have been performed and identified COH29 binding is specific to RRM2. These studies further confirm a V-shaped binding pocket of RRM2 with COH29. Preliminary data suggest that COH29 represents a promising new class of RR inhibitors with the advantages of (a) a unique mechanism and target specificity that interferes with the radical transfer pathway at the RRM1-RRM2 interface, (b) greater potency than HU in the sub-µM range of IC50, and (c) avoiding iron chelating-related side effects compared to 3-AP. Therefore, our objectives are to optimize the properties of COH29 into a viable candidate as a future anticancer drug targeting over expressed RR based cancers. (This project was supported by NIH grant CA 127541) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3258. doi:10.1158/1538-7445.AM2011-3258