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  • Review Article
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The resurgence of covalent drugs

Nature Reviews Drug Discovery volume 10, pages 307–317 (2011)Cite this article

Subjects

Key Points

  • Covalent drugs block protein function by forming a specific bond between the ligand and target protein.

  • A covalent mechanism of action can provide many pharmacological advantages over a reversible mechanism of action; these advantages include enhanced potency, selectivity and prolonged duration of action.

  • As a therapeutic class, covalent drugs have made a major impact on human health, as indicated by the many examples of US Food and Drug Administration (FDA)-approved covalent drugs in various indications.

  • Many of the approved covalent drugs were discovered through serendipity. Computer-assisted drug design has led to a predictable means of creating a new generation of covalent drugs that have been termed 'targeted covalent inhibitors'.

  • Several targeted covalent inhibitors are in late-stage clinical development and are showing encouraging efficacy.

  • This Review surveys the prevalence and pharmacological advantages of covalent drugs, and discusses how potential risks and challenges may be addressed through innovative design, as well as the broad opportunities presented by targeted covalent inhibitors.

Abstract

Covalent drugs haveproved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This Review surveys the prevalence and pharmacological advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.

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Figure 1: Prevalence of approved covalent drugs by therapeutic indication (n= 39).
Figure 2: Timeline of covalent drugs.
Figure 3: Special considerations in the discovery and development of targeted covalent inhibitors.
Figure 4: X-ray complexes of targeted covalent inhibitors covalently bound to their targets.

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Acknowledgements

We would like to thank the Avila team for their help and encouragement in the preparation of this manuscript. We would also like to thank K. Houk, D. Fry and A. Wissner for their helpful comments.

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Authors and Affiliations

  1. Avila Therapeutics, 100 Beaver Street, Waltham, 02453, Massachusetts, USA

    Juswinder Singh & Russell C. Petter

  2. School of Pharmacy, University of Washington, Seattle, 98195, Washington, USA

    Thomas A. Baillie

  3. Department of Chemistry, Boston University, Metcalf Science Center, 590 Commonwealth Avenue, Boston, 02215, Massachusetts, USA

    Adrian Whitty

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  1. Juswinder Singh
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Correspondence to Juswinder Singh.

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Competing interests

Juswinder Singh and Russell C. Petter are employees of Avila Therapeutics.

Thomas A. Baillie and Adrian Whitty are paid consultants of Avila Therapeutics.

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DATABASES

RCSB Protein Data Bank (PDB) 

3OYP

2JIV

FURTHER INFORMATION

ChEMBL-og — Kinase Inhibitors in Clinical Development

Glossary

Idiosyncratic drug-related toxicity

(IDT). A rare adverse event that is observed after administration of certain drugs and is frequently immunogenic in origin.

Targeted covalent inhibitor

An inhibitor bearing a bond-forming functional group of low reactivity that, following binding to the target protein, is positioned to react rapidly with a specific non-catalytic residue at the target site. For the purposes of this Review, it is assumed that covalent modification is essentially irreversible.

Covalent inhibitor

An inhibitor that reacts with its target protein to form a covalent complex in which the protein has lost its function. Covalent inhibitors can be reversible or irreversible, depending on the rate of the reverse reaction. In this Review, we predominantly consider irreversible inhibitors, and so the terms 'covalent inhibitor' and 'irreversible inhibitor' are used interchangeably.

Irreversible inhibitor

An inhibitor that possesses an off-rate that is slow relative to the rate of re-synthesis of the target protein in vivo, so that once the target protein is inhibited, it does not regain activity.

Re-synthesis rate

The rate at which a cell and/or organism replaces a protein target with freshly synthesized functional protein. The re-synthesis rate defines the rate at which an irreversibly inhibited protein target will recover activity in vivo, once the inhibitor is no longer present.

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Singh, J., Petter, R., Baillie, T. et al. The resurgence of covalent drugs. Nat Rev Drug Discov 10, 307–317 (2011). https://doi.org/10.1038/nrd3410

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