Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present

Abstract

Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme. In this review, we discuss the mechanisms and clinical applications of classic nucleoside analog inhibitors of hRRM1 (large catalytic subunit), including gemcitabine and clofarabine, as well as inhibitors of the hRRM2 (free radical housing small subunit), including triapine and hydroxyurea. Additionally, we discuss novel approaches to targeting RR and the discovery of new classes of hRR inhibitors.

CHK1 Inhibition Overcomes Gemcitabine Resistance in Non-Small Cell Lung Cancer Cell A549

“…RR is a tetramer consisting of two homodimeric subunits. Every subunit contains ribonucleotide reductase regulatory subunit M1 (RRM1) and RRM2 (Bothou 2021, Huff 2022). Jin et al (Jin 2020) found differential enrichment in cell cycle, P53 signaling pathway, DNA replication, apoptosis, and cancer pathways in patients with high expression of RRM2.…”

Glutathione Protects other Cellular Thiols against Oxidation by CuII‐Dp44mT

“…[8,9] An important proposed mechanism is intracellular Fe binding and inhibition of ribonucleotide reductase via electron transfer to its tyrosine radical. [6,[10][11][12] However, due to drawbacks such as low efficacy and methemoglobinemia, other heterocyclic TSC have been developed since then. [6,13] Further development of Triapine leads, among others, to the di-2-pyridylketone-4,4-dimethyl-thiosemicarbazone (Dp44mT), a widely studied TSC.…”

“…Triapine (3‐aminopyridine‐2‐carboxaldehyde thiosemicarbazone) was the first compound of this family to enter clinical trials [8,9] . An important proposed mechanism is intracellular Fe binding and inhibition of ribonucleotide reductase via electron transfer to its tyrosine radical [6,10–12] . However, due to drawbacks such as low efficacy and methemoglobinemia, other heterocyclic TSC have been developed since then [6,13] …”

Expanding the Scope of Group Transfer Radical Reaction: Toward the Synthesis of Fluorinated Nucleoside Analogues Incorporating Difluorophosphonylated Allylic Ether Moieties

“… Indeed, the most well-known blockbusters like gemcitabine and sofosbuvir contain fluorine atoms on the ribose ring to improve the metabolic stability, the lipophilic character, and lock nucleoside conformations, all of which modulate their pharmacokinetic properties. However, very few organofluorinated group-containing nucleosides were described, with one of the most representative examples being the ribonucleotide reductase inhibitor tezacitabine functionalized by a monofluoro alkene . Furthermore, RNA-type oligonucleotides (ONs) have also rapidly emerged as pivotal molecules in medicinal chemistry as illustrated with the recent mRNA vaccines developed during the COVID-19 pandemic.…”