Editorial pubs.acs.org/crt
Toxicology Strategies for Drug Discovery - Present and Future: Introduction
T
he Tufts Center for the Study of Drug Development has calculated the cost of bringing a new drug to market in the range of $2.5 billion, with attrition of clinical candidates accounting for much of that cost.1 Attrition due to safety concerns occurs at all stages of drug development and constitutes a large fraction of the failure rate of new chemical entities. Thus, a general goal of the majority of pharmaceutical companies is to develop approaches to predict the safety/ toxicity of drug candidates at an early point in the overall process, often referred to as “discovery toxicology.” The goal of safety studies in the discovery stage is to integrate information from a variety of liability identification study types and ultimately assess if a new compound has the liability profile to become a drug. The studies are ideally employed such that they can be an integral part of the overall candidate optimization process. These early studies are designed to identify liabilities or hazards; the process of translation from hazard identification to risk assessment requires understanding of the therapeutic use of the drug candidate as well as a prediction of the human pharmacokinetic and absorption/ distribution/metabolism/excretion (ADME) properties of the candidate. The focus on what assays to employ and how to use them differs among scientists and companies.1 Chemical Research in Toxicology has recently published a number of papers, both Research Articles and Perspectives, in the area of predictive drug safety, 2−5 as well as high-throughput approaches to prediction of the toxicity of environmental chemicals.6,7 This special issue features a collection of manuscripts that cover aspects of drug discovery toxicology, spanning from in silico predictions all the way to overall risk assessment. The papers covering liability identification were chosen on topics where there have been recent advances in our understanding of how to characterize a known liability, whether through the advancement in the biochemistry of the liability, e.g., BSEP/ MRP3 inhibition and hepatotoxicity,2 or advancement in models used to characterize the liability, e.g., the use in zebrafish in the characterization of developmental abnormalities. Overall, this article collection should be a useful reference for scientists working in drug discovery chemistry and toxicology, as well as those interested in the relevance of the mechanisms of toxicity and in applying concepts to other potential toxicants.6,7
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AUTHOR INFORMATION
Corresponding Author
*Tel: 615-322-2261. Fax: 615-343-0704. E-mail: f.guengerich@ vanderbilt.edu. Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) (2015) Optimizing your ADME/Tox operations, Genet. Eng. Biotechnol. News. (2) Thompson, R. A., Isin, E. M., Li, Y., Weidolf, L., Page, K., Wilson, I., Swallow, S., Middleton, B., Stahl, S., Foster, A. J., Dolgos, H., Weaver, R., and Kenna, J. G. (2012) In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem. Res. Toxicol. 25, 1616−1632. (3) Verbist, B. M., Verheyen, G. R., Vervoort, L., Crabbe, M., Beerens, D., Bosmans, C., Jaensch, S., Osselaer, S., Talloen, W., Van den Wyngaert, I., Van Hecke, G., Wuyts, D., Consortium, Q., Van Goethem, F., and Gohlmann, H. W. (2015) Integrating highdimensional transcriptomics and image analysis tools into early safety screening: Proof of concept for a new early drug development strategy. Chem. Res. Toxicol. 28, 1914−1925. (4) Garcia-Serna, R., Vidal, D., Remez, N., and Mestres, J. (2015) Large-scale predictive drug safety: from structural alerts to biological mechanisms. Chem. Res. Toxicol. 28, 1875−1887. (5) Hu, B., Gifford, E., Wang, H., Bailey, W., and Johnson, T. (2015) Analysis of the ToxCast chemical-assay space using the Comparative Toxicogenomics Database. Chem. Res. Toxicol. 28, 2210−2223. (6) Kavlock, R., Chandler, K., Houck, K., Hunter, S., Judson, R., Kleinstreuer, N., Knudsen, T., Martin, M., Padilla, S., Reif, D., Richard, A., Rotroff, D., Sipes, N., and Dix, D. (2012) Update on EPA’s ToxCast program: providing high throughput decision support tools for chemical risk management. Chem. Res. Toxicol. 25, 1287−1302. (7) Liu, J., Mansouri, K., Judson, R. S., Martin, M. T., Hong, H., Chen, M., Xu, X., Thomas, R. S., and Shah, I. (2015) Predicting hepatotoxicity using ToxCast in vitro bioactivity and chemical structure. Chem. Res. Toxicol. 28, 738−751.
W. Griffith Humphreys† Yvonne Will‡ F. Peter Guengerich*,§ †
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, United States ‡ Drug Safety Research and Development, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States § Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 © 2016 American Chemical Society
Special Issue: Toxicology Strategies for Drug Discovery - Present and Future Published: April 18, 2016 437
DOI: 10.1021/acs.chemrestox.6b00049 Chem. Res. Toxicol. 2016, 29, 437−437
