Small Molecules, Big Impact: Expanding the Universe of Targets

Last month, I had the opportunity to moderate a panel titled “Discussing the Current Landscape of Protein Degradation and Expanding the Disease Scope Beyond Oncological Targets” at the Protein Degradation & Targeting Undruggables Congress in Boston. Panelists Danette Daniels , Beth J Hoffman , and Charles Lin engaged in a thoughtful discussion on how companies are navigating this new modality and the challenges, tools, and opportunities to expand its use.

Targeted protein degradation (TPD), at a very high level, is a compelling, novel modality: You can use small molecules to eradicate intractable proteins that aren’t able to be addressed or are poorly addressed by other modalities, delivering a potentially transformative new way to fight disease. These protein degraders have the power of a genetic-like knockdown or knockout with the flexibility of small molecule drug discovery, development, and commercialization. Thus far, the vast majority of companies advancing this modality have mainly focused on addressing oncology targets; but TPD itself is really a disease-, protein-, and tissue-agnostic approach, and some companies, with Kymera Therapeutics in a leading role, have also ventured into other therapeutic areas such as immunology and inflammation.

The conference panelists began the session with a discussion of why and how TPD is being applied to oncology targets; many of the protein degraders in the clinic were noted in recent Nature Reviews: Nature Reviews Clinical Oncology and Nature Reviews Drug Discovery ?(which includes three programs from our pipeline). The panelists agreed the risk/reward profile for TPD favors oncology due to the existence of numerous clinically validated targets coupled with the limitations of existing cancer therapies in key areas such as safety (selectivity), resistance, potency, and durability. Oncology therefore presents a prime opportunity to drive meaningful improvements in patient care while validating a new therapeutic modality. Our panel also discussed some of the challenges or risks of deploying TPD in oncology, such as the potential risk of resistance to the novel mechanism and understanding the long-term impact of co-opting E3 ligases that serve “many other protein clients.” Kymera is attempting to mitigate these potential risks through focused platform investments in the areas of novel E3 ligase discovery and characterization.

As noted, given the mechanism and applicability of the technology, there is also a significant opportunity to apply TPD beyond oncology, and we discussed the many technical considerations that need to be assessed when developing degrader medicines in other therapeutic areas. Some key elements included fully assessing the suitability of the target for TPD by ensuring both its intracellular accessibility and multi-function activity. Additional key dimensions to understand include protein turnover rates and ligandability, as well as target and ligase expression in all relevant cell and tissue types. Together these considerations inform novel target selection approaches and highlight the advantages of degrader medicines over other modalities such as small molecule inhibitors, as seen with the development of Kymera’s IRAK4 degrader, which recently completed a successful initial proof of concept Phase 1 clinical trial. IRAK4 serves as a key node in an inflammation signaling pathway where extensive validation has been conducted, most recently with clinical-stage small molecule kinase inhibitors. However, because the IRAK4 protein has both scaffolding and kinase function activities, these small molecule kinase inhibitors only partially block the activity of this disease-causing protein; whereas our IRAK4 degrader eliminates the protein entirely and thereby fully eliminates its activity.

Additionally, the field continues to drive science forward to de-risk the platform by utilizing innovative computational and research tools to develop new ways to harness the body’s recycling system. And Kymera and others are also identifying novel molecular glues that can access validated targets in oncology, immunology, and beyond (e.g., potentially rare disease, cardiovascular, CNS) that don't have discrete binders to those proteins, further expanding the universe of druggable targets.

I would like to thank the panelists for their time and insights, and the conference organizers for coordinating a great session. There continues to be energy and opportunity in the field of TPD, with several new companies launching each year, new drug candidates rapidly advancing to the clinic, and novel platform approaches creating promising new opportunities to impact the lives of patients with serious diseases.?