July 21, 2025

(Shutterstock)

In 2013, the National Institutes of Health (NIH) launched Illuminating the Druggable Genome (IDG), a program to help researchers learn about understudied proteins within the three most commonly drug-targeted protein families: G-protein coupled receptors (GPCRs), ion channels and protein kinases. Supported by the NIH Common Fund and led by NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases, IDG was designed to venture into unfamiliar areas. The program “attempted to shift science toward the unknown,” said Tudor Oprea, M.D., Ph.D., an IDG grantee who is currently the chief executive officer of Expert Systems, Inc., a company combining human and artificial intelligence (AI) to accelerate drug discovery.

During its 10-year span (the typical length of most Common Fund programs), IDG provided many funding opportunities and encouraged smaller awards, such as R03 Small Research Grants, which could then be built into larger awards like R01s. While the funding for the program has ended, many researchers see the beginning of a new era of drug discovery, as the tools created and data gathered through IDG can support future studies into drug targets once considered too high risk and low reward.

“IDG provided a lot of new resources and tools for the community as a whole to advance knowledge on potentially valuable drug targets that weren’t being explored in the past,” noted Shawn Gomez, Eng.Sc.D., an IDG grantee at The University of North Carolina (UNC). “A big part of this effort was to help other groups and de-risk some of the effort needed to propose new studies.”

One such resource is Pharos, an online portal that provides dozens of data sets compiled by IDG investigators. NCATS built Pharos with collaborators from The University of New Mexico, University of Miami, Icahn School of Medicine at Mount Sinai, Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen, and the European Molecular Biology Laboratory at the European Bioinformatics Institute.

Two other IDG-sponsored resources originated in the laboratory of Bryan Roth, M.D., Ph.D., at the UNC School of Medicine. TRUPATH allows users to investigate G proteins downstream of GPCRs, and the PRESTO-Tango GPCR Kit, developed with funds from both UNC and IDG, can help researchers identify which small molecules or natural products are able to bind to specific GPCRs — a key step in the drug discovery process. Both are available through Addgene, a nonprofit repository that to date has shipped more than 130,000 plasmids to thousands of institutions in more than 50 countries.

The list of useful resources created through IDG is broad. Among them are data tools like TIN-X, the Target Importance and Novelty Explorer, which helps to unveil links between diseases and potential drug targets. TIGA, short for Target Illumination GWAS Analytics, filters and ranks likely gene–trait connections to help prioritize drug targets. The Dark Kinase Knowledge Base and Protein Kinase Ontology Browser offer powerful tools for exploring the roughly 160 kinases (enzymes that send signals and control complex processes in cells) for which the function in human biology is poorly understood.

Together, the many resources developed as part of the IDG provide “a conceptual starting point for generating new testable hypotheses on understudied kinases and pseudokinases and for drug discovery efforts,” said Natarajan Kannan, Ph.D., an IDG grantee at the University of Georgia.

IDG Finds Serendipitous Success

Along the way, several IDG-supported groups have found unexpected success. While looking at a screen of molecular areas altered by SARS-CoV-2, scientists found an understudied kinase that was part of the virus’s replication process. IDG’s Kinase Data and Resource Generating Centers revealed several compounds that worked on that kinase.

“It opened a whole new pathway,” said Gomez. “But nobody was looking at this kinase in general without IDG. Now it’s on the way to possibly becoming a therapeutic.”

In the final few years of the program, Roth and his team received a supplement from IDG to solve the structures of 15 orphan or understudied GPCRs. While doing that work, Roth came up with an experimental platform that he thought could be used to study peripheral mind-body interactions. Until now, no systems have existed that are specific to areas outside the brain and spinal cord. He is now working on a possible treatment for intractable peripheral pain using this platform. “The work was entirely funded by the IDG and never would have been done if not for the program,” Roth said.

A Promising but Uncertain Future

Today, projects enabled by IDG are ongoing with support from academia, industry and private foundations. Ben Major, Ph.D., another IDG awardee within the kinase group, along with Kannan and Gomez, are working on a protein interaction map that shows which proteins are within a few nanometers of a given dark (e.g., understudied) kinase. Finding where these kinases live in the context of other better-understood signaling networks may help connect the dark kinases to key pathways and processes. The project has generated a huge amount of data that will eventually be publicly available. Likewise, Kannan is leveraging advances in AI and large protein language models for predicting functions of understudied protein kinases and ion channels.

Other groups also are continuing to improve their data sets — including ones that have already been used to study Alzheimer’s disease. These sets could prove especially valuable as AI and machine learning become more common. “We have a lot of knowledge about 10% of the therapeutic targets in the human genome and not a lot of knowledge about the other 90%, which may be equally or even more important as therapeutic targets,” said Roth. “Without initiatives like IDG, training sets become even more lopsided.”

Questions remain about the future of some of the tools created through IDG. The hope is that platforms like Pharos can find enough funding to sustain themselves and that IDG was, ultimately, a springboard — a beginning rather than an end. “Most people focus on things that are well-worn because there is a lot of information and it’s easier to get the data and get grants,” said NCATS program director Karlie Sharma, Ph.D. “IDG was a case study to show that you can pull some of the dark proteins and really connect them with human disease and make a pretty large impact.”

To learn more about IDG and its work, read the special series published in Drug Discovery Today by Sharma and her colleagues and check out other NCATS news stories.