Perspective

† Author for correspondence

Pfizer Global Research and Development, Groton, CT 06340, USA.

Email the corresponding author at doug.johnson@pfizer.com

The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA

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Benjamin F Cravatt

† Author for correspondence

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Email the corresponding author at cravatt@scripps.edu

Published Online:14 Jun 2010https://doi.org/10.4155/fmc.10.21

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Abstract

This article presents several covalent inhibitors, including examples of successful drugs, as well as highly selective, irreversible inhibitors of emerging therapeutic targets, such as fatty acid amide hydolase. Covalent inhibitors have many desirable features, including increased biochemical efficiency of target disruption, less sensitivity toward pharmacokinetic parameters and increased duration of action that outlasts the pharmacokinetics of the compound. Safety concerns that must be mitigated include lack of specificity and the potential immunogenicity of protein–inhibitor adduct(s). Particular attention will be given to recent technologies, such as activity-based protein profiling, which allow one to define the proteome-wide selectivity patterns for covalent inhibitors in vitro and in vivo. For instance, any covalent inhibitor can, in principle, be modified with a ‘clickable’ tag to generate an activity probe that is almost indistinguishable from the original agent. These probes can be applied to any living system across a broad dose range to fully inventory their on and off targets. The substantial number of drugs on the market today that act by a covalent mechanism belies historical prejudices against the development of irreversibly acting therapeutic small molecules. Emerging proteomic technologies offer a means to systematically discriminate safe (selective) versus deleterious (nonselective) covalent inhibitors and thus should inspire their future design and development.

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Published online 14 June 2010

Published in print June 2010

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Financial & competing interests disclosure

Douglas Johnson is an employee and shareholder of Pfizer Global Research and Development. Benjamin Cravatt is a professor at The Scripps Research Institute in La Jolla, CA, USA, and has served as a consultant with Pfizer Global Research and Development since 2003. This work was supported in part by the NIH, the Helen L Dorris Institute for the Study of Neurological and Psychiatric Disorders in Children and Adolescents, and The Skaggs Institute for Chemical Biology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Strategies for discovering and derisking covalent, irreversible enzyme inhibitors

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