Identifying New Drug Targets by Illuminating the Druggable Genome

Jun 18, 2020

Guest Blog by Karlie R. Sharma, Ph.D., Program Officer, National Center for Advancing Translational Sciences, NIH

Results from the Human Genome Project have revealed that the human genome contains around 20,000 genes. Of these, approximately 4,500 genes are considered part of the “druggable genome,” defined as the subset of the human genome that expresses proteins that are able to bind drug-like molecules. However, existing clinical drugs only target a few hundred of these genes, leaving a large swath of proteins that have no clinical therapeutics available. Among these druggable protein targets, there is a subset of about 400 proteins that still remain largely understudied, but that have high potential to impact health once disease associations are made. Three well-established druggable protein families—the ion channels, G-protein-coupled receptors and protein kinases—have been identified to contain adequate numbers of understudied members and to have broad significance in human health. Further investigation is warranted to discover crucial knowledge about the function of understudied members of these protein families and to elucidate their roles in health and disease.

To improve our scientific understanding of understudied members of these three protein families, the National Institutes of Health (NIH) Common Fund launched the Illuminating the Druggable Genome (IDG) Program in 2014. The overall goal of the IDG Program, which is coordinated by the NIH’s National Center for Advancing Translational Sciences (NCATS) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), is to catalyze research in areas of biology that are currently understudied but that have high potential to impact human health by (1) identifying biochemical, cellular, or animal model phenotypes for understudied proteins from druggable gene families, (2) enabling further investigation of those proteins by providing reagents and tools, and (3) generating, maintaining, and facilitating the use of a minable knowledge base.

Through the IDG program, IDG researchers are using tools such as high-throughput drug screens, proteomics approaches, CRISPR technology and mass spectrometry, among others, to develop novel resources for the scientific community, including small businesses and the pharmaceutical industry, that gives them the ability to explore previously understudied biology with the potential to rapidly impact human health.

The program produces several research resources around understudied proteins, such as reagents, bioinformatics tools and data.  A key resource from this program, Pharos, aggregates protein information from several sources, giving researchers easy access to in depth protein data and resources, allowing them to enhance their research by providing information on ligands, protein-protein interactions, tissue expression and disease associations, among others, and help identify new targets of interest. In addition, IDG-funded investigators established scalable technology platforms and streamlined experimental workflows for large-scale functional studies of poorly characterized and/or un-annotated proteins encoded by the druggable genome. These resources are now available via for use by the scientific community, with the IDG Program continuing to build on the knowledge and tools developed and generate, aggregate, analyze, and disseminate knowledge and tools around understudied proteins.

Although the IDG Program focuses on kinases, GPCRs and ion channels, it complements other current efforts to illuminate the dark side of the genome. The ReSOLUTE project, a program out of Europe’s innovative medicines initiative (IMI), focuses on generating reagents that allow the scientific community to work more efficiently with solute carriers and make use of them as targets for drug development. Also recently, ZebiAI Therapeutics has teamed up with Google Accelerated Science to apply machine learning to accelerate research into and further characterize the function of understudied proteins and validate novel therapeutic targets. These initiatives are but a few examples of the increased interest and opportunities in discovering functions around the dark side of the genome.

It is clear that, through the development of novel tools and resources, these dark protein targets now have the potential to become properly illuminated and, possibly, lead the way to the development of treatments and cures for some of our most intractable diseases.

About the Author:

Karlie R. Sharma, Ph.D.
Program Officer, National Center for Advancing Translational Sciences, NIH

Dr. Karlie Sharma joined the National Center for Advancing Translational Sciences (NCATS) in January 2017 and is the NCATS representative and co-coordinator for the Common Fund program “Illuminating the Druggable Genome” (IDG), a program focused on understanding the properties and functions of proteins that are currently unannotated within commonly drug-targeted protein families.  Dr. Sharma is also involved in a number of additional initiatives at NCATS, including the Discovering New Therapeutic Uses for Existing Molecules program, the Small Business Technology Transfer (STTR) and Small Business Innovation Research (STTR) program and is co-lead on a number of Machine Intelligence related activities.

Dr. Sharma received her Ph.D. in Molecular Physiology and Biophysics from Baylor College of Medicine in Houston, Texas in 2013 for her work on myotonic dystrophy.  Prior to joining NCATS, Dr. Sharma was a postdoctoral fellow in the Laboratory of Host Defenses headed by Dr. Harry Malech at the National Institute of Allergy and Infectious Diseases.  Her research was primarily focused on studying autoimmune disease, specifically graft versus host disease, and developing therapies to treat and/or prevent occurrence of the disease. 

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