A better way to find drug targets
A better way to find drug targets
- New study refines the definition of the ‘druggable genome’ – the set of genes that encode promising drug targets.
- Updated genotyping array with enriched ‘druggable genome’ content allows researchers to identify new disease relationships for drug targets.
- Findings underscore the power of genotyping studies to inform drug development.
29 March 2017 – New research from EMBL-EBI, University College London and others delivers updated ‘druggable genome’ data and tools to match drug targets to diseases, develop new medicines and find new uses for previously developed ones. The study, published in Science Translational Medicine, provides new resources to promote drug-discovery research.
Genome wide association studies (GWAS) are used to associate small differences in DNA sequences, called SNPs, with diseases. These studies provide a valuable source of evidence for drug discovery, with information that can guide researchers to potential targets for drugs. However, only a limited number of genes compose the set of proteins that could be the targets for medicines.
In this study, researchers from several organisations combined forces to redefine the ‘druggable genome’ – the list of genes that make proteins one could target with a drug. Previous estimates of the druggable genome focused primarily on small-molecule drugs – the updated estimate now includes targets for larger ‘biological’ drugs, like antibodies.
“We wanted to ensure that researchers are aware of all the most promising drug targets so they can focus their efforts and follow up the best leads,” explains Anna Gaulton of EMBL-EBI. “Some of these ‘druggable genes’ have been identified for a disease association in GWAS, but this is only a fraction of the druggable genome – which we estimate to be close to 4500 genes.”
“One factor might be that certain commonly used genotyping arrays used in GWAS don’t necessarily cover all the genes that might make good drug targets in detail,” adds EMBL-EBI alumnus John Overington, now at BenevolentAI. “Our work was used to guide the development of a new genotyping array that includes more comprehensive coverage of variants in the druggable genes.”
“Having up-to-date tools and data is really important if we want to help people find new targets,” says Chris Finan of Institute of Cardiovascular Science, University College London. “But it’s also important for drug repurposing – it lets you see if an existing drug might be effective on a different disease.”
Aroon Hingorani, Institute of Cardiovascular Science and Farr Institute, University College London explains that the new array could make a positive difference in drug target identification and validation. “Using genotyping arrays that offer comprehensive coverage of the druggable genome in data-rich collections such as national biobanks or routine electronic health record datasets would be an asset to drug discovery. Unlike single disease GWAS, these collections capture a huge range of physiological, biochemical, imaging phenotypes, as well as clinical diagnoses all at the same time.”
“We believe this approach provides a route to enhancing drug-development success rates, and helps address the efficiency and innovation gap in drug development,” adds Juan Pablo Casas of the Farr Institute and Institute of Health Informatics, University College London.
Today’s study provides further validation for the approach of utilising genomic variation data in projects like Open Targets, and adds valuable tools and data to the public domain.
Finan C, Gaulton A, et al. (2017) The druggable genome and support for target identification and validation in drug development. Science Translational Medicine 9:eaag1166. DOI: 10.1126/scitranslmed.aag1166 [link: http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aag1166]
This work was supported by Rosetrees Trust, British Heart Foundation, Wellcome Trust and National Institute for Health Research (NIHR).
Data and tools
The redefined druggable genome is available from the authors upon request.
- Researchers using genome-wide association study (GWAS) data have ‘rediscovered’ many known drug targets, highlighting the potential of genetic studies to match drug targets to diseases correctly.
- About a fifth of gene–disease associations discovered in GWAS point to regions of the human genome containing a single gene. About a third of these regions encode ‘druggable’ proteins that would be strong candidates for drug targets.
- This study provides plausible drug-repurposing opportunities, based on discordant pairings of drug indications and disease associations for over 100 drug targets.
- The approach published today presents opportunities to develop new therapeutics. For example, genetic associations in cardiovascular conditions mapped to 135 druggable genes and 512 compounds that reached advanced clinical development, including 168 licensed drugs.