Significant numbers of human diseases are caused by proteins or mechanisms that cannot be treated via traditional drugs or gene therapy. Many of these conditions are considered untreatable as they are caused by pathologies for which we lack drug development options, such as protein misfolding, proteins with hidden active sites, defective protein-protein interactions or where the targets are “other cellular entities” (e.g., RNAs and small molecules). With the recent development of novel emerging therapies to overcome many of these druggability challenges, the field is primed to open up new classes of molecular entities and explore expanded horizons outside of the traditional small molecule discovery tract.

Some precedent has already been set for these novel treatment approaches such as the development of immunotherapies in cancer and the development of Proteolysis targeting chimeras (PROTAC), a technology/modality which allows the targeting of intractable proteins for proteasomal degradation. The need for alternative treatment modalities against intractable disease targets is not unique to any one disease field, and it is expected that many other disease areas could benefit from development of novel treatment modalities.

With this in mind, we plan to host a workshop with the goal of identifying pain points for developing treatments against targets traditionally considered intractable to current methods of drug discovery. In this workshop, we will focus on (1) identifying protein families, molecular entities, and disease areas most in need of innovative therapeutic modalities, (2) identifying new or emerging technologies that could be leveraged to address limitations of current treatment modalities, and (3) identifying gaps or pressure points preventing or slowing the development of strategies for treating human diseases associated with ‘intractable’ targets. It is expected that outcomes from this workshop will inform future directions for pursuing targets considered ‘intractable’ and the exploration of innovative modalities, thereby expanding the pool of therapeutic approaches for treating human diseases. 

Workshop Outline: Full Agenda

Day 1: Targets (11:00-4:00 PM EST)

Session 1: RNA – traditionally considered an undruggable target due to folding complexities and expression levels, RNAs have been implicated in many diseases. Identifying treatment methods of targeting RNA would be highly beneficial to many disorders.

Session 2: Protein-Protein Interactions and Protein Stabilization – dysfunctional protein interactions as well as protein misfolding and destabilization can have a profound impact on human health. At this time, treatment options for these diseases are limited.

Session 3: Other Targets – there are many additional protein targets and molecular entities that contribute to human disease but have limited treatment modalities. This session will touch on some of these targets.

Day 2: Modalities (11:00-4:00 PM EST)

Session 1: Existing Modalities to Leverage for Novel Targets – this session will focus on therapeutic modalities that may already exist but could possibly be leveraged to address novel targets within human disease.

Session 2: Novel Modalities – speakers in this session will go over novel methods for targeting disease outside of the traditional small molecule drug discovery pathway.

Session 3: Novel Drug Delivery Methods – this session will focus on new and/or more effective methods of drug delivery for human diseases.

For more information:

If you have any questions about the workshop, please contact Karlie Sharma (karlie.sharma@nih.gov, 240.381.3118).

Sign language interpreting and CART services are available upon request to participate in this event. Individuals needing either of these services and/or other reasonable accommodations should contact Karlie Sharma. Requests should be made at least five days in advance. To access Telecommunications Relay Services (TRS), call 711.

Graphics for this workshop were generated by the DALL-E neural network on OpenAI:

Aditya Ramesh et. al. Zero-Shot Text-to-Image Generation. (2021) arXiv:2102.12092

This workshop was organized by the following individuals:

Rose Aurigemma, PhD (NCI)
Associate Director, Developmental Therapeutics Program, aurigemr@mail.nih.gov

Jim Boyce, PhD (NIAID)
Program Officer, Drug Discovery, jim.boyce@nih.gov

David Jett, PhD (NINDS)
Health Scientist Administrator, Division of Translational Research, jettd@ninds.nih.gov

Abir Malik, MS (NCATS)
Program Analyst, Office of Drug Development Partnership Programs, abir.malik@nih.gov

Rebecca Roof, PhD (NINDS)
Program Director, Division of Translational Research, rebecca.roof@nih.gov

Karlie Sharma, PhD (NCATS)
Program Director, Office of Drug Development Partnership Programs, karlie.sharma@nih.gov

Sundar Venkatachalam, PhD (NCI)
Chief, Preclinical Therapeutics Grants Branch, sundar.venkatachalam@nih.gov

Sharad Verma, PhD (NCI)
Special Assistant to the Associate Director, Developmental Therapeutics Program, sharad.verma@nih.gov