Expanding the Druggable Space With Degradation-Based Therapies

Degradation-based therapies are emerging as a promising therapeutic approach to address undruggable targets and improve therapeutic effects for classically druggable targets. But, despite their potential, several challenges remain.

PhoreMost is working to overcome these issues and advance the discovery of novel targets with its SITESEEKER® degrader discovery platform and the recently introduced GlueSEEKER™ platform, which enables the systematic discovery of molecular glue degraders.

Technology Networks spoke with Dr. Christian Dillon, chief scientific officer at PhoreMost, to learn more about degradation-based therapies, the challenges associated with their discovery and how innovative solutions are helping to realize the potential of this promising class of therapeutics.

Karen Steward (KS): Can you tell us about degradation-based therapies, how they work and why they’re becoming an important approach for “undruggable” targets?

Christian Dillon (CD): Degradation-based therapies are part of a wider subset of therapies that rely on induced proximity. Unlike traditional therapeutics, which inhibit disease-causing proteins, this approach involves hijacking normal regulatory processes in a cell and reprograming them to modulate disease-causing targets specifically in ways that were unthinkable just a few years ago.

By bringing a disease-associated target into close proximity with an E3 ubiquitin ligase, degradation-based therapies trigger the ubiquitination of the target and its subsequent removal via the cell’s protein disposal machinery – the proteasome.

There are two types of degrader therapeutics that are currently attracting interest – bivalent degraders and monovalent molecular glues. Bivalent degrader molecules such as proteolysis targeting chimeras (PROTACs) are chimeric molecules with a linker in the middle. One end binds to the disease-associated target, and the other binds to an E3 ligase to induce ubiquitination. Molecular glue degraders are smaller structures that “glue” the target protein to the E3 ligase.

One of the most exciting aspects of these new modalities is their potential to expand the scope of drug targets or the type of targets we can tackle – many of which were previously considered undruggable due to a lack of well-defined drug pockets or a lack of enzymatic activity. In addition, there may also be opportunities to tackle more established and classically druggable targets using protein degradation, where removal of the protein causes a different therapeutic effect, typically due to non-enzymatic activities such as scaffolding functions.

KS: How is PhoreMost’s SITESEEKER technology helping to advance discovery and development of cancer therapies in this space?

CD: Despite the promise of degrader-based therapies, most rely on just two E3 ligases – Cereblon (CRBN) and Von Hippel-Lindau (VHL), both of which have limitations including potential toxicities, resistance and target scope, and in the case of VHL, a greater challenge to achieve oral bioavailability. There has been great interest in expanding the E3 ligase toolbox for degradation-based therapies; for example, identifying novel E3 ligases to improve the target scope and tissue-specific properties.

Our SITESEEKER technology systematically unmasks new druggable sites across the human proteome and directly links them to therapeutic functions in a physiologically relevant phenotypic screening context. We have recently deployed our SITESEEKER platform to unlock new E3 ligases for targeted protein degradation and enable them for drug discovery, identifying a number of new ligases with optimized properties to enable oncology drug discovery. We have achieved fantastic proof-of-concept data in vivo and are now developing our pipeline of assets towards the clinic.

KS: What challenges and hurdles remain in this work being translated into real-world therapies that are available to patients?

CD: Many of the challenges seen in the development of degrader-based therapeutics are those associated with the development of any new molecular entity; it is crucial to understand the degradation mechanism and biology of both the target and E3 ligase. It has taken many years to reach the level of understanding we now have for CRBN and VHL, and the same will be true for any new E3 ligases, which will pose a significant challenge. Preclinically, the biological processes that underpin the efficacy of PROTACs are complex, requiring extensive screening cascade assays and significant structural and computational modeling.

Bifunctional molecules are large in terms of their molecular weight, going beyond Lipinski’s rule of five. This often leads to poor permeability and bioavailability, resulting in challenges associated with achieving an optimal drug metabolism and pharmacokinetic profile. This can be achieved for CRBN-based degraders, but evidence is more limited for VHL-based degraders, requiring researchers to consider alternative delivery routes.

We also need to understand the therapeutic index and potential off-target effects – are other proteins being degraded, and if so, in which tissues? Selection of the right toxicity and safety species in preclinical development is important to enable accurate prediction of degraded targets.

KS: How have the rapid developments in AI and deep learning capabilities in recent years impacted PhoreMost?

CD: AI and deep learning have had a transformational impact on our business in multiple areas. Firstly, AI-based algorithms support the design and optimization of our PROTEINi libraries – libraries of mini proteins that enable the identification of new druggable targets. We also incorporate advanced structural prediction models to understand the translational path of targets identified using our SITESEEKER platform.

Moving into drug discovery, we use AI for enhanced virtual screening of small molecules and extensive in silico modeling, including molecular dynamics, to aid optimization. It is also crucial to be able to model target-molecule-ligase ternary complexes effectively as part of the optimization process of degradation-based therapies. As AI technologies continue to evolve, we will no doubt see further applications, such as predicting drug efficacy and toxicities, become more prevalent.

KS: What do you see as the most exciting development area for therapeutic drugs for the future, in particular for the treatment of cancers?

CD: Degradation-based therapies are an exciting area of new drug discovery, offering new modalities to expand the druggable space. Human and functional genomic studies have led to a very good understanding of the key drivers in cancer biology, and their interactions with the immune system within the tumor microenvironment, with many interesting targets having an inverse relationship with classic druggability criteria.

A protein degradation approach has the potential to tackle this challenge and improve patient benefit. The first wave of targets has been classically druggable, where degradation-based therapies offer an alternative, and perhaps superior, mechanism of action to existing approved drugs. However, we are now increasingly seeing the promise of targeted protein degradation being realized with more challenging disease-relevant targets being addressed.

Molecular glues hold great promise in the development of oncology therapeutics, but most discoveries to date have relied heavily on serendipity, and the field needs an innovative approach to drive the rational design of new molecules. We have developed our GlueSEEKER platform to tackle this challenge as a method to identify new molecular glue targets systematically, potentially for any E3 ligase – an approach which holds great promise for the future.

Dr. Christian Dillon was speaking to Dr. Karen Steward, Senior Scientific Specialist for Technology Networks.

About the interviewee

Dr. Christian Dillon is chief scientific officer at PhoreMost, with 20 years’ experience working at the interface between academia and industry. Previously, Christian served as associate director at Cancer Research UK’s Therapeutic Discovery Laboratories, where he led a number of drug discovery alliances with pharmaceutical partners and oversaw the progression of its portfolio of small molecule and therapeutic antibody projects.