The Quest for Innovative Molecular Treatment Modalities for Intractable Disease Targets Workshop gathered many experts and enthusiasts from academia and industry to explore and discuss the latest advancements and discoveries in the realm of undruggable targets and alternative treatments. The workshop aimed to provide a platform for knowledge sharing and collaboration, and participants engaged in a series of presentations and discussions around novel targets for disease treatment, such as RNAs, Intrinsically Disordered Proteins, organelles and cellular structural components, among other targets, and explored novel modalities and drug delivery methods that could be leveraged to treat intractable human diseases. Through these discussions, the workshop aimed to identify pain points for developing treatments against targets traditionally considered intractable using current methods of drug discovery. This summary will highlight the key takeaways from the workshop and provide insights into the advancements of different targets and modalities.

Brian Lanman, PhD, from Amgen, Inc. kicked off day one by presenting combination approaches to potentially identify new targetable pockets on “undruggable” proteins under new conditions. This includes “cryptic” binding sites that are revealed when a protein is mutated. After this exciting discussion, an RNA-focused session showcased the druggability of RNA. As only ~1% of the human genome encodes protein while around 80% of the genome encodes RNA, RNA is considered a very promising option for treating disease. RNA can be targeted in several forms including tRNA, RNA in the ribosome, mRNA, pre-mRNA, and more. In addition, the ribosome itself could be considered a drug target due to its unique structure presenting vast highly expansive targetable binding pockets for small molecules. This discussion was followed by the protein stabilization session, where it was indicated that approximately half of human disease is caused by protein misfolding. Three major types of diseases are associated with protein misfolding that include (1) loss of function and abnormal trafficking such as sickle cell anemia, (2) lipid-lipid phase separation states caused by RNA binding proteins such as frontotemporal dementia, and (3) self-propagating amyloids such as prion disease. At this time, there are no treatments for these diseases beyond combination therapies, as protein tangles are often made up of several misfolded proteins. The first day wrapped up with the other novel targets session, which focused on targeting cellular systems as opposed to a specific molecular target. Some examples from this session include targeting lipid rafts in pain, the golgi apparatus to treat Alzheimer’s Disease and intermediate filaments in rare disease. The day concluded with a discussion around the need for biomarkers to target many of these diseases early or prior to symptoms.

Michelle Arkin, PhD, from UCSF gave the keynote presentation for day two, which focused on drug development failure caused by incomplete target validation or undruggability of the target. She went into further detail to explain that “undruggability” is often the result of proteins that are either too flat for a drug to bind or so disordered that they can only bind to their protein target. This led to the next session, repurposing current modalities, where degraders and molecular glues were presented as novel and evolving modalities that could open up new opportunities for revisiting ‘older’ targets, where previous modalities may have been insufficient. In addition, off-shoots of these technologies, such as deubiquitinase-targeted chimeras (DUBTACs) for targeted protein stabilization, were presented, highlighting the potential for modification of existing technologies to address new targets. This was followed by the novel modality session, which touched on the need for an intimate understanding of the disease state and a clearly defined mechanism of perturbation.  It was emphasized that basic drug discovery platforms remain underdeveloped (structural biology, screening etc.), hampering faster and safer drug development, and that alignment of features that constitute “drug-likedness” should be considered high priority. The workshop concluded with the novel drug delivery session, where the speakers discussed different alternative drug delivery mechanisms, such as photoactivation of liposomes, novel bioengineered microbiome-based therapeutics delivery, tissue specific nanoparticles, and leucine zippers. These drug delivery methods and others can better allow us to direct treatments to tissues, control drug dosing, and facilitate reduction or removal of treatment after the treatment course.

This workshop provided a valuable opportunity for participants to deepen their understanding of undruggable targets and alternative modalities through engaging presentations and discussions. The science and technology discussed during this workshop is constantly advancing, but overall, the outcomes of this workshop have provided an informative platform that will assist researchers in pursuing targets considered ‘intractable’, and explore innovative modalities, thereby expanding the therapeutic landscape for treating human diseases. The workshop was a great success, and we are excited to see how this research and information positively shapes the scientific community.

Workshop recordings can be found here.