Targeting ribonucleotide reductase for cancer therapy.

INTRODUCTION: Ribonucleotide reductase (RR) is a unique enzyme, because it is responsible for reducing ribonucleotides to their corresponding deoxyribonucleotides, which are the building blocks required for DNA replication and repair. Dysregulated RR activity is associated with genomic instability, malignant transformation and cancer development. The use of RR inhibitors, either as a single agent or combined with other therapies, has proven to be a promising approach for treating solid tumors and hematological malignancies. AREAS COVERED: This review covers recent publications in the area of RR, which include: i) the structure, function and regulation of RR; ii) the roles of RR in cancer development; iii) the classification, mechanisms and clinical application of RR inhibitors for cancer therapy and iv) strategies for developing novel RR inhibitors in the future. EXPERT OPINION: Exploring the possible nonenzymatic roles of RR subunit proteins in carcinogenesis may lead to new rationales for developing novel anticancer drugs. Updated information about the structure and holoenzyme models of RR will help in identifying potential sites in the protein that could be targets for novel RR inhibitors. Determining RR activity and subunit levels in clinical samples will provide a rational platform for developing personalized cancer therapies that use RR inhibitors.