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. 2019 Feb 1;167(2):593-603.
doi: 10.1093/toxsci/kfy265.

Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence

Aimee M Deaton  1 , Fan Fan  1 , Wei Zhang  1 , Phuong A Nguyen  1 , Lucas D Ward  1 , Paul Nioi  1
Affiliations

Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence

Aimee M Deaton et al. Toxicol Sci. .

Abstract

Safety-related drug failures remain a major challenge for the pharmaceutical industry. One approach to ensuring drug safety involves assessing small molecule drug specificity by examining the ability of a drug candidate to interact with a panel of "off-target" proteins, referred to as secondary pharmacology screening. Information from human genetics and pharmacology can be used to select proteins associated with adverse effects for such screening. In an analysis of marketed drugs, we found a clear relationship between the genetic and pharmacological phenotypes of a drug's off-target proteins and the observed drug side effects. In addition to using this phenotypic information for the selection of secondary pharmacology screens, we also show that it can be used to help identify drug off-target protein interactions responsible for drug-related adverse events. We anticipate that this phenotype-driven approach to secondary pharmacology screening will help to reduce safety-related drug failures due to drug off-target protein interactions.

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Figures

Figure 1.
Figure 1.
Results for off-target phenotypes in logistic regression models. Showing all phenotypes where off-target phenotypes had p < .05. Circular points indicate odds ratios from the models; error bars are 95% confidence intervals. ***p < .001, **p < .01, *p < .05.
Figure 2.
Figure 2.
Selection and characteristics of phenotype-focused secondary pharmacology screen. A, Selection of targets to include on secondary pharmacology screen, using phenotypes from human genetics and drug indications. B, Protein class distribution. C, Distribution of key safety phenotypes for the 70 proteins included on our proposed secondary pharmacology panel.
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