The human genome has revealed a great deal about the human proteome, though significant portions remain understudied. Only a subset of expressed proteins demonstrates the requisite properties to serve as targets for the development of therapeutics. Many bona fide drug targets likely remain to be discovered in the "Druggable Genome" (DG), which can be defined as a subset of the ~20,000 genes in the human genome encoding proteins that have the potential to bind drug-like molecules. The term "drug-like" refers to the physical, biochemical, and pharmacological attributes of small molecule compounds that are generally recognized to be required for efficacious clinical drugs in humans. While the number of proteins in the DG is upwards of 3,000, the existing clinical pharmacopeia is represented by only a few hundred targets, leaving a huge swath of biology that remains unexploited.
The discovery of a disease association or the development of a useful tool reagent can accelerate research into a previous understudied protein, such as was the case for BRAF. Thus, while many interesting and critical biological processes and potential therapeutic avenues remain unexplored because an initial, catalyzing event has not yet occurred, the IDG Program will address this bottleneck by systematically querying these understudied proteins to find phenotypic associations and develop useful research tools.
While at the informatics level, genome-, and proteome-wide tools can collate information and query all proteins, technical feasibility necessitates a narrower focus of experimental efforts into protein families for which there are definable understudied members along with existing technologies that can be readily adapted at the scale necessary for wholesale elucidation of their function and generation of tools. During the Pilot Phase of the IDG, it was determined that the experimental focus of the IDG will be on the understudied members in the families of non-olfactory GPCRs, ion channels, and protein kinases, as these families contain adequate numbers of understudied members and are well-established druggable families with high potential to impact human health once disease associations are made. It is expected that experimental priorities of the proteins within these three families will change over the period of the project.
The IDG Consortium is expected to transform research by revealing a number of new activities and potential drug targets amongst these understudied proteins. Moreover, it is anticipated that the IDG Consortium will enhance our understanding of on- and off-target effects by establishing functional relationships among understudied members of the commonly targeted protein families.
Thus, the overall long-term goals of the IDG Program are two-fold:
To advance research through the development, broad dissemination, and use of community scientific resources to study human proteins for which publicly available information or active research is lacking to catalyze the discovery of novel biology, with a particular focus on understudied members of the protein kinase, ion channel, and non-olfactory GPCR families.
To demonstrate the feasibility and benefits of illuminating the roles of IDG proteins, permitting the expansion of such approaches to a broader array of protein families beyond the three families of proteins in the IDG Program.
The current IDG Consortium is made up of projects funded under the following FOAs:
The Knowledge Management Center (KMC; RFA-RM-16-024) aggregates knowledge from a protein-centric viewpoint across the entire human proteome, with an emphasis on the understudied non-olfactory GPCRs, protein kinases, and ion channels that are the focus of the experimental initiative. The KMC develops a knowledge portal (Pharos) that includes the aggregated data and metadata, a query interface, and deployed informatics tools along with community access to resources developed by the IDG Consortium. The main goal of Pharos is to provide access to aggregated data and IDG resources for the broad scientific community.
The Data and Resource Generation Centers (DRGCs; RFA-RM-16-026) generate and validate new knowledge and/or tools relevant to the understudied members of the protein kinase, ion channel, and non-olfactory GPCR families with the intent of broadly and rapidly disseminating knowledge and tools to the research community. As one of the essential goals of this program, NIH intends that tools and reagents generated by the IDG Consortium will be broadly available and distributed at minimal cost, and without undue intellectual property constraints, so that they can be used as widely as possible, enabling further investigation of understudied proteins by the larger scientific community.
The Resource Dissemination and Outreach Center (RDOC; RFA-RM-16-025) assists in the dissemination of data and tools and the overall coordination of the IDG Consortium. The IDG RDOC works with all IDG Consortium investigators to collect, curate, and disseminate information regarding critical tools and reagents being developed by the IDG Consortium through the IDG Portal.
Cutting Edge Informatics Tools Awards (CEITs; RFA-RM-18-011) are intended to add to the informatics capabilities of the IDG program. These new tools will augment the capability of the KMC as well as the broader IDG Consortium in the following ways: (1) by developing and deploying tools to enhance the community's ability to process, analyze, and visualize IDG data, (2) to prioritize new data resources and methods to be incorporated into Pharos that will strengthen predictions about physiological and disease associations around the understudied proteins, and (3) by developing methods to prioritize understudied IDG families (non-olfactory GPCRs, protein kinases, and ion channels) for deeper study using experimental assays both within the IDG pipeline or by the larger community.
Objectives and Scope
Multiple community workshops held during the pilot phase of the IDG program concluded that understudied proteins become “illuminated” when (1) there are tools to study the protein (e.g., tools that modulate protein activity) and (2) there is biochemical, cellular, or animal model evidence of disease/physiological relevance.
The goal of this FOA is to fund Small Business Technology Transfer (STTR) projects involving IDG-eligible proteins. The STTR program, also known as America’s Seed Fund, is one of the largest sources of early-stage capital for technology commercialization in the United States. This program allows US-owned and operated small businesses to engage in federal research and development that has a strong potential for commercialization. The STTR program is divided into three phases. Phase-I is to establish the technical merit, feasibility, and commercial potential of the proposed research efforts and to determine the quality of performance of the small business awardee organization prior to providing further federal support in Phase II. Work in phase-II continues the R&D efforts initiated in Phase I. Funding is based on the results achieved in Phase I and the scientific and technical merit and commercial potential of the project proposed in Phase II. The final phase (Phase-III) is for the small business to pursue commercialization objectives resulting from the Phase I/II research and development activities with private entities. The NIH STTR program does not fund Phase III, and NIH does not generally provide any Phase III funding to small businesses.
Projects under this FOA would go beyond what the IDG’s Centers can accomplish and/or to validate and demonstrate the commercial utility of IDG proteins, reagents, data, and approaches. Specifically, this FOA solicits STTR projects that focus on the following protein classes.
IDG-eligible proteins that will be supported under this FOA:
ADGRA1, ADGRB2, ADGRB3, ADGRD1, ADGRD2, ADGRE1, ADGRE2, ADGRE3, ADGRF1, ADGRF2, ADGRF3, ADGRF4, ADGRF5, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRG7, FZD10, GNRHR2, GPR101, GPR12, GPR135, GPR137, GPR139, GPR141, GPR142, GPR143, GPR146, GPR149, GPR150, GPR151, GPR152, GPR153, GPR156, GPR157, GPR160, GPR162, GPR171, GPR173, GPR174, GPR18, GPR19, GPR20, GPR21, GPR22, GPR25, GPR26, GPR27, GPR31, GPR32, GPR32P1, GPR34, GPR37L1, GPR39, GPR4, GPR45, GPR50, GPR52, GPR6, GPR61, GPR62, GPR63, GPR68, GPR75, GPR78, GPR82, GPR85, GPR87, GPR88, GPRC5A, GPRC5B, GPRC5C, GPRC5D, HCAR1, HCAR3, HTR1E, HTR5A, LPAR6, MAS1L, MRGPRE, MRGPRF, MRGPRG, MRGPRX2, MRGPRX3, MRGPRX4, MTNR1A, NPBWR1, NPBWR2, NPY2R, NPY5R, OXER1, OXGR1, P2RY10, P2RY11, PROKR1, QRFPR, RXFP3, RXFP4, SUCNR1, TAAR2, TAAR3, TAAR8, TAAR9, TAS2R1, TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31, TAS2R39, TAS2R4, TAS2R40, TAS2R41, TAS2R42, TAS2R43, TAS2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TPRA1
ASIC4, BEST4, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, CACNG1, CACNG3, CACNG4, CACNG5, CACNG6, CACNG7, CACNG8, CATSPER2, CHRNA10, CHRNA2, CHRNB1, CHRND, CLCA2, CLCA4, CLCC1, CLCN6, CLCNKA, CLIC2, CLIC3, CLIC5, CLIC6, CNGA4, FAM26D, FAM26E, FAM26F, FXYD3, FXYD7, GABRA5, GABRG1, GABRP, GABRR1, GLRA3, GLRA4, GLRB, GPR89A, GPR89B, GRID1, GRIK3, HTR3C, HTR3D, HTR3E, KCNA6, KCNA7, KCNAB2, KCNAB3, KCNC4, KCND1, KCNG2, KCNG3, KCNG4, KCNH4, KCNH6, KCNH8, KCNIP1, KCNIP4, KCNJ14, KCNJ15, KCNJ18, KCNK12, KCNK4, KCNK7, KCNMB3, KCNMB4, KCNN1, KCNS1, KCNS2, KCNS3, KCNT1, KCNT2, KCNV1, LRRC38, LRRC55, PANX2, PKD1L2, PKD1L3, PKD2L2, PLLP, SCN2B, SCN3B, SCN7A, SCNN1B, SCNN1D, SLC26A1, TMC3, TMC4, TMC5, TMC7, TMEM38B, TMEM63A, TMEM63B, TMEM63C, TTYH1, TTYH2
ADCK1, ADCK2, ADCK5, ALPK2, ALPK3, BCKDK, CAMK1D, CAMK1G, CAMKK1, CAMKV, CDC42BPB, CDC42BPG, CDK10, CDK11B, CDK14, CDK15, CDK17, CDK18, CDKL1, CDKL2, CDKL3, CDKL4, CLK3, CLK4, COQ8A, COQ8B, CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A2, DSTYK, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K, ERN2, HIPK4, LMTK3, LRRK1, LTK, MAP3K10, MAP3K14, MAPK15, MAPK4, MARK4, MAST2, MAST3, MAST4, MKNK2, NEK10, NEK11, NEK4, NEK5, NEK6, NEK7, NIM1K, NRBP2, NRK, PAK3, PAK5, PAK6, PAN3, PDIK1L, PHKG1, PHKG2, PI4KA, PIK3C2B, PIK3C2G, PIP4K2C, PIP5K1A, PIP5K1B, PKMYT1, PKN3, PNCK, POMK, PRKACB, PRKACG, PRKCQ, PRPF4B, PSKH1, PSKH2, PXK, RIOK1, RIOK2, RIOK3, RPS6KC1, RPS6KL1, SBK1, SBK2, SBK3, SCYL1, SCYL2, SCYL3, SGK223, SGK494, SRPK3, STK17A, STK3, STK31, STK32A, STK32B, STK32C, STK33, STK36, STK38L, STK40, STKLD1, TBCK, TESK1, TESK2, TLK1, TLK2, TP53RK, TSSK1B, TSSK3, TSSK4, TSSK6, TTBK1, TTBK2, ULK4, VRK2, VRK3, WEE2, WNK2
Recall that Phase-I projects minimally demonstrate basic proof-of-concept (POC), feasibility and potential commercial value. Whereas phase-II projects expand R&D efforts initiated in Phase I to strengthen the scientific and technical merit of the project while including a clear and concise commercialization plan. Potential projects could include but are not limited to the following topic areas:
- Isolation and purification of understudied proteins and initial in vitro characterization in the context of a marketed product
- Development of accessory reagents (e.g., antibodies, peptide fragments, labeled versions of the protein, etc.) for use in downstream studies
- Assay development, optimization, and validation with the intent of using these assays for further advancement of selected protein(s) or as stand-alone marketed products
- Validation or placement of protein(s) in signaling cascades, including upstream signals and downstream activities with the intent of initiating a biomarker or drug discovery project
- Characterization of cell and tissue-specific protein expression, localization, and function in native environments
- Use of data mining and experimental validation to analyze IDG-generated data sets and other public data resources to identify and study protein-protein interaction networks or generate hypotheses about the function of IDG protein(s)
- Use of IDG-generated (or other) tools to validate preliminary disease or physiological associations with IDG proteins in animal models, biomimetic systems, or ex vivo human samples
- Studies to establish preliminary structure-activity-relationships (SAR) between functions of an understudied protein and its ligands (e.g., small molecules, macrocycles, synthetic peptides)
- Experimental validation of predictive protein models produced by the IDG
- Medicinal chemistry efforts leveraging existing SAR of a chemical scaffold to optimize a lead preclinical candidate including characterization of efficacy as well as absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties
- Protein engineering to produce a lead clinical candidate molecule that modulates the activity of key regulators of tissue and organ regeneration
- Pharmacological testing of novel preclinical lead candidates in state of the art efficacy models as well as the evaluation of novel models to better predict the efficacy of compounds (e.g. next-generation animal models, microfluidic-based 3D human organoid systems, etc.)
- Generation of labeled ligands, proteins, or biologics for use as clinical biomarkers such as in PET-imaging studies;
- Construction of ready-to-use reagent kits for the study of IDG proteins.
All relevant datasets, tools, and capabilities associated with understudied proteins collected by the IDG can be found in Pharos. Applicants are strongly encouraged to use available resources in Pharos when applying to this FOA as part of the justification for the approach selected and/or to assist in accomplishing the goals of the project. Applicants should also review DruggableGenome, the IDG Consortium website, to ensure proposed work does not overlap with ongoing studies being performed by the IDG Consortium.
The following will not be considered for support under this FOA:
- Projects where most of the proposed work focuses on proteins outside of those listed above
- Applications that propose purely clinical studies involving IDG-eligible protein(s) and that meet the definition of an NIH clinical trial
- Any approach that does not primarily focus on elucidating the function of IDG-eligible proteins or their potential use as a commercial product
- Projects that propose work identical to that currently being performed by the IDG Consortium (consult DruggableGenome for a list of current IDG Consortium projects)
The applicant should have sufficient information to give confidence to the reviewers that the proposed work is feasible and that data derived from the project would likely be suitable as preliminary validation data of commercial potential either as initial proof-of-concept (phase-I) or subsequent preclinical development (phase-II). Applicants should identify the IDG-eligible protein(s) they propose to study and indicate how their project will help to elucidate the function of the understudied protein(s). Projects should help to elucidate the function and/or structure of those protein(s) in relevant models that will ultimately inform human biology.
It is important to note that while modeling and informatics activities within the IDG consortium are not necessarily meant for starting drug discovery and development projects, projects under this FOA should have a reasonable expectation of commercial value. At this point, most activities will be focused on finding the role of understudied proteins in physiology and disease, identifying relevant pathways, or identifying ligands or other modulators. Proposed studies must be applicable to at least one protein from the above list of IDG-eligible proteins to be considered for funding.
The National Institute of Dental and Craniofacial Research (NIDCR) is the lead federal agency for scientific research on dental, oral, and craniofacial health and disease. NIDCR encourages projects on IDG-eligible proteins that are relevant to the human oral cavity, or that may illuminate pathways for future intervention for oral and craniofacial development, or to help treat dental diseases or to improve dental, oral and craniofacial health. Projects should have a high probability of commercialization either as assays, diagnostics or therapeutics. Applicants are strongly encouraged to contact program staff for consultation before submitting applications. The NIDCR does not accept Phase IIB (competing renewal) applications.
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) encourages applicants to discuss the relevance of proposed projects to the mission of the NIDDK with program staff before preparing an application. The NIDDK is exclusively interested in disease-focused translational research relevant to its mission which includes obesity, diabetes, diabetic complications, endocrine diseases, liver and digestive diseases, nutrition, kidney and urological diseases, hematology, and inborn errors of metabolism. For Phase I applications, experiments must test the validity of IDG-eligible proteins for relevance in these areas; Phase II applications must contain strong preliminary data supporting their relevance to the interests of the NIDDK. For additional information on disease areas of interest to the NIDDK, please see https://www.niddk.nih.gov/research-funding/research-programs/Pages/default.aspx. Projects in areas that are primarily within the missions of other Institutes or Centers (ICs) of the NIH are not appropriate for assignment to the NIDDK.
The National Institute of Mental Health (NIMH) encourages applicants to discuss the relevance of proposed projects to the mission of the NIMH with program staff before preparing an application. The NIMH is interested in the development of technologies that will enable discoveries of the role of these understudied proteins in neuroscience and in psychiatric diseases and for identifying relevant pathways. Additionally, NIMH is interested in the identification of ligands or other modulators associated with these proteins. For additional information on neuroscience or disease areas of interest to the NIMH, please see https://www.nimh.nih.gov/about/strategic-planning-reports/index.shtml
The National Center for Advancing Translational Sciences (NCATS) strives to develop innovations to reduce, remove or bypass costly and time-consuming bottlenecks in the translational research pipeline to speed the delivery of new drugs, diagnostics and medical devices to patients. The NCATS approach is generally disease agnostic and does not favor applications in any disease area over another. NCATS seeks projects on IDG-eligible proteins that will transform the translational science process so that new treatments and cures for disease can be delivered to patients more efficiently. Projects of most interest to NCATS include those that focus on drug discovery and development, biomedical, clinical and health research informatics and clinical, dissemination and implementation research. Applicants are strongly encouraged to contact program staff.
See Section VIII. Other Information for award authorities and regulations.