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Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases

Key Points

  • Nucleoside and nucleotide analogues are largely used in the treatment of cancer and viral infections.

  • A large number of novel compounds continue to be synthesized and evaluated both by academia and the pharmaceutical industry, which underlines the important interest in this family of drugs.

  • Different strategies are being used to develop new agents, such as pronucleotides and conjugates.

  • New agents are expected to have different resistance profiles compared to already approved agents.

  • New interferon-free regimens to cure hepatitis C virus infection are likely to contain a potent and pan-genotypic active nucleoside or nucleotide analogue. Two of these — sofosbuvir and mericitabine — are in Phase III clinical trials.

Abstract

Nucleoside analogues have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with cancer or viral infections. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Here, we review new nucleoside analogues and associated compounds that are currently in preclinical or clinical development for the treatment of cancer and viral infections, and that aim to provide increased response rates and reduced side effects. We also highlight the different approaches used in the development of these drugs and the potential of personalized therapy.

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Figure 1: General structural and chemical modifications of nucleoside and nucleotide analogues.
Figure 2: Mechanism of action of nucleoside analogues.
Figure 3: Chemical structures of representative anticancer and antiviral nucleoside and nucleotide analogues in development.
Figure 4: The pronucleotide strategy.

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Acknowledgements

The authors acknowledge the support of the Association pour la Recherche sur le Cancer (ARC) and the Ligue contre le Cancer. L.P.J. acknowledges the Olav Raagholt and Gerd Meidel Raagholt Foundation for Research (Olav Raagholt og Gerd Meidel Raagholts stiftelse for medisinsk forskning).

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Correspondence to Lars Petter Jordheim, David Durantel, Fabien Zoulim or Charles Dumontet.

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Competing interests

F.Z. has received consulting/speaking fees from Gilead, Bristol-Myers Squibb and Janssen Cilag.

F.Z. and D.D. have received research grants from Roche.

C.D. and L.P.J. have received research grants from Clavis Pharma.

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Supplementary information S1 (table)

Currently approved nucleos(t)ide analogues and indications (PDF 113 kb)

Supplementary information S2 (table)

Main enzymatic activities targeted by nucleos(t)ide analogues for different chronic viruses (PDF 118 kb)

Supplementary information S3 (table)

Mutations in different viral polymerases conferring resistance to nucleos(t)ide analogues (PDF 138 kb)

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Associations between genetic variants and response to nucleoside analogue therapy in cancer patients (PDF 147 kb)

Glossary

Ribonucleotide reductase

A complex intracellular enzyme that converts ribonucleoside diphosphates into deoxyribonucleoside diphosphates, and is targeted by anticancer agents such as gemcitabine.

Nucleobase

A nitrogen-containing heterocyclic compound that can be grouped into purines (adenine and guanine) and pyrimidines (cytosine, thymine and uracil).

Dose adaptation

Determination of the dose that should be administered to a patient based on predicted or observed toxicity.

Demethylating agents

Compounds that modify the methylation status of regulatory sequences in DNA, thereby modifying the levels of expression of the corresponding gene.

Nucleoside transporters

Membrane pumps that allow the uptake and/or the efflux of nucleosides by cells.

Chain elongation

The increase in length of DNA or RNA strands during replication or transcription.

Phenotypic assays

Assays in which biological function or cell response is measured as an index of drug action.

Pronucleotides

Phosphorylated nucleosides in which the phosphate is linked to a protective group to increase diffusion of the nucleoside across the cell membrane.

Nucleophilic attack

A chemical reaction in which a negatively charged entity forms a bond with a positively charged atom.

Prodrugs

Compounds that are administered as inactive pharmacological entities that are then metabolized in vivo into an active compound.

Sustained viral response

The absence of detectable virus in the blood for up to 6 months after treatment.

First-pass hepatic metabolism

The uptake and metabolism of an orally administered drug by enzymes in the liver, which reduces the concentration of the drug in the systemic circulation.

Phase 0 trial

A first-in-human clinical trial that is carried out to determine the pharmacodynamic and pharmacokinetic properties of a drug.

Drug repositioning

A strategy in which drugs that were initially developed in a given indication are subsequently applied to a novel indication.

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Jordheim, L., Durantel, D., Zoulim, F. et al. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov 12, 447–464 (2013). https://doi.org/10.1038/nrd4010

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