Application of Emerging Toxicity Screens in Drug Discovery: Challenges and Implications

Abstract

EditorialThe discovery and development of drugs remain very challenging, time consuming, expensive and hampered by low success rates. It can take up to 12-15 years to bring a drug to market with an estimated cost in excess of US$800 million [1][2][3]. Safety issues remain a major cause of the latestage attrition and low success rate. Discovering safety issues late in development is potentially financially devastating for a company. It is therefore imperative that potential safety issues are identified early. In this article, we highlight some selected in silico, in vitro and in vivo approaches that are being used to predict potential toxicity early in the drug-discovery phase with the hope of reducing late-stage attrition and improving success rates.Classical toxicity testing relies primarily on observing adverse biological responses in homogeneous groups of animals exposed to high doses of a test agent. However, these tests provide little information on modes and mechanisms of action, information critical for understanding interspecies differences in toxicity and the translation of preclinical data to humans. Moreover, these preclinical studies are expensive, time consuming and require large numbers of animals. The current focus and urgency in the pharmaceutical industry is to shorten the timelines for all aspects of drug discovery and to improve the ability to filter out early potential safety issues. We are therefore seeing an increasing interest and focus of developing high-throughput screening (HTS) approaches. These early HTS approaches that are completed in the early drug-discovery phase even before the efficacy screenings and not necessarily linked to the mechanistic-driven strategy will gain increasing importance in the coming years in allowing early identification of potential toxicity issues. In addition, the continuing understanding and advancement of 'omics' (i.e., genomics, proteomics and metabolonomics) technologies will elucidate patterns of biomarkers changes that aid the prediction of different toxicities. These approaches include promoter-reporter assays, gene expression arrays and bioanalytical methods. In silico and in vitro tests have the advantage of being able to rapidly evaluate large numbers of chemicals, greatly reducing animal use and accelerating lead identification and optimization. The potential of in silico approaches was heralded with great fanfare with the promise of rapid impact in decreasing attrition and increasing productivity. Not surprisingly, in recent years, we have seen a more reasoned and rational expectation of the potential of in silico predictive models and the increasing development and application of both in silico models and toxicity databases for a number of toxicity end points (e.g., mutagenicity, carcinogenicity, skin sensitization, reproductive and cardiac toxicity). In addition, pharma companies are now increasingly utilizing their in-house data for the development of both generic and chemotype-specific in silico models. Examples of some of the commercially a...