Safety

Manually-curated safety data to support target prioritisation

Overview

Throughout the drug discovery and development process, target safety assessments help with understanding the role of the drug target in normal physiology and potential unintended adverse consequences and safety liabilities when modulating the target with a chemical compound or drug (Brennan, 2017).

To support target prioritisation, we have manually curated experimental data and insights from publications and other well-known sources of target safety and toxicity data, including the ToxCast, AOPWiki and PharmGKB (Open Targets downstream analysis of the toxicity datasets).

Safety data is available on the target profile page and can be accessed to provide a systematic view of potentially relevant target safety liabilities.

Computational pipelines and datasets

Target safety datasets are mapped to the correct Ensembl gene ID and ingested during our initial pipeline steps to enrich the target annotation object. The data is available for download as part of the target core annotation from our data download page.

Publications

Bowes J, Brown AJ, Hamon J, Jarolimek W, Sridhar A, Waldron G, Whitebread S. Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nat Rev Drug Discov. 2012 Dec;11(12):909-22. doi: 10.1038/nrd3845. PMID: 23197038.

Brennan R.J. (2017) Target Safety Assessment: Strategies and Resources. In: Gautier JC. (eds) Drug Safety Evaluation. Methods in Molecular Biology, vol 1641. Humana Press, New York, NY. doi: 10.1007/978-1-4939-7172-5_12

Force T, Kolaja KL. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat Rev Drug Discov. 2011 Feb;10(2):111-26. doi: 10.1038/nrd3252. PMID: 21283106.

Ann M. Richard, Richard S. Judson, Keith A. Houck, Christopher M. Grulke, Patra Volarath, Inthirany Thillainadarajah, Chihae Yang, James Rathman, Matthew T. Martin, John F. Wambaugh, Thomas B. Knudsen, Jayaram Kancherla, Kamel Mansouri, Grace Patlewicz, Antony J. Williams, Stephen B. Little, Kevin M. Crofton, and Russell S. Thomas. ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology. Chemical Research in Toxicology 2016 29 (8), 1225-1251. doi: 10.1021/acs.chemrestox.6b00135. PMID: 27367298.

Lamore SD, Ahlberg E, Boyer S, Lamb ML, Hortigon-Vinagre MP, Rodriguez V, Smith GL, Sagemark J, Carlsson L, Bates SM, Choy AL, Stålring J, Scott CW, Peters MF. Deconvoluting Kinase Inhibitor Induced Cardiotoxicity. Toxicol Sci. 2017 Jul 1;158(1):213-226. doi: 10.1093/toxsci/kfx082. PMID: 28453775; PMCID: PMC5837613.

Lynch JJ 3rd, Van Vleet TR, Mittelstadt SW, Blomme EAG. Potential functional and pathological side effects related to off-target pharmacological activity. J Pharmacol Toxicol Methods. 2017 Sep;87:108-126. doi: 10.1016/j.vascn.2017.02.020. PMID: 28216264.

Urban L, Whitebread S, Hamon J et al. Screening for safety-relevant off-target affinities. In: Polypharmacology in Drug Discovery. Peters JU (Ed.). John Wiley and Sons, NJ, USA (2012). doi: 10.1002/9781118098141.ch2.

Society for Advancement of AOPs. AOP-Wiki. 2023. Available from http://aopwiki.org.