A Platform That Could Help Identify and Target the “Undruggable”

Many proteins are linked to disease pathology and are therefore potential targets for therapeutics. However, using conventional technologies, some proteins are undetectable due to their interfacing with other proteins, forming complexes. Such proteins have been deemed “undruggable” previously, and their lack of detection has meant that potential therapeutic options for diseases such as cancer are being missed out. 

We spoke to Neil Torbett, PhD, CEO of PhoreMost to learn more about “undruggable” targets and how the SITESEEKER® platform can identify these novel sites in the human proteome.

Molly Campbell (MC): Having worked in biotech for over 15 years, can you talk to me about how the industry has evolved during this time? Are there any particular breakthroughs that you think have been critical for the industry to get to where it is now?

Neil Torbett (NT): Looking further back, my first scientific job was based at the Human Genome Mapping Project Resource Centre at the Wellcome Trust Genome campus. I remember it being tremendously exciting to think that the whole human genome was being sequenced. Since then, having access to the whole genome sequence has opened the way for many advances at the “protein” level which has been key to understanding disease. This has all been taken to the next level over the past couple of years with advances in protein structure prediction which will undoubtedly be a massive driver of innovation in the coming years.

MC: What do we mean by “the undruggable”, and why is this currently a major barrier for drug development and patient care?

NT: Industry has still largely been focused on drugging what we might call classically druggable targets (i.e., enzymes which have a druggable active site). However, many proteins which are clearly linked to disease have remained intractable through conventional means. These proteins work in networks by interfacing with other proteins in the cell via protein-protein interactions and it is these critical interfaces which have remained elusive to systematic discovery, therefore defined as “undruggable”.

MC: Can you explain how the SITESEEKER® platform functions to identified druggable sites that can’t be readily seen using conventional technologies?

NT: SITESEEKER® enables us to systematically search for and identify novel druggable sites across the entire human proteome for future therapy. At the heart of our approach is the simple idea that the huge diversity of protein shapes present in nature can be exploited to find new druggable sites. Over the past five years, PhoreMost has developed the platform such that millions of diverse protein shapes (or PROTEINi®) can be interrogated for cellular activity within the context of disease-relevant phenotypic screening.

Our platform is able to identify phenotypically active PROTEINi® forming a rational basis to identify novel targets and, importantly, binding pockets through which they function. The PROTEINi®-target pairing is a powerful tool to trigger first-in-class drug discovery programs through either conventional means or next generation approaches. Indeed, by linking disease-relevant phenotypes to druggable “pocket” identification, SITESEEKER® has the potential to unlock the power of protein structure prediction for next generation drug design.

MC: Phoremost is “committed to forging a new model of drug discovery” by working in partnership with both academia and industry. Can you talk about how industry and academic partners are harnessing SITESEEKER?

NT: The SITESEEKER® approach to target identification can be applied to any disease setting. In order to maximize the potential of our platform at PhoreMost, our philosophy is that developing therapeutics is best done in partnership, where synergistic expertise can be brought together in a unique way to tackle complex diseases. Our academic partners provide access to fundamental disease and target biology expertise which is invaluable to our internal project progression. We also have a number of active partnerships across the Pharma and Biotech sectors including with Otsuka, Oxford Biomedica, XtalPi and Boehringer Ingelheim. Recently, we have announced exciting collaborations with POLARISqb and NeoCura, with more to come! 

MC: What are the greatest challenges PhoreMost encounters in drug R&D, and how is it working to overcome them?

NT: For a small biotech PhoreMost’s platform spans many disciplines, from target screening all the way through to small molecule development and beyond. So navigating both the complexity of our organization and also defining our focus areas has been challenging as our company has evolved. We are so lucky at PhoreMost to have an amazing team of dedicated scientists that have broken through many obstacles.

The particular challenge of translating phenotypic peptide – target interface information into developable small molecule hit matter is one that has been historically difficult. However, this is where PhoreMost, both internally and in partnership is using next generation technologies such as protein structure prediction, advanced AI-based virtual screening and other structural insights to progress targets that were previously unchartered.

MC: What does the future look like for PhoreMost?

NT: The future for PhoreMost is incredibly exciting especially following a significant year for the Company which included a successful £33M Series B investment round and the relocation of our HQ to a new bespoke state-of-the-art facility in south Cambridge.

Firstly, our lead program (allosteric PLK1 inhibitor, partnered with Sentinel Oncology) is progressing towards clinical entry. This will be massive milestone for our company.

Our internal program development is otherwise currently heavily focused within the Targeted Protein Degradation (TPD) area. Here PhoreMost are set to make some major advance for the field which is attracting intense interest.

Degradation-based therapies, such as bifunctional small molecules, which recruit an E3 ligase to destroy (rather than inhibit) a therapeutic protein of interest (POI) are becoming an integral approach to tackling previously undruggable targets. Despite there being over 600 E3 ligases, industry is still heavily reliant on using a single ligase, Cereblon, within degrader-based drug development. At PhoreMost, we are seeking to change this key limitation. We have deployed our SITESEEKER® technology towards the discovery of functionally active “degrader” PROTEINi® which operate through a wide variety of E3 ligases to degrade recruitable POIs. From these insights, we are able to progress small molecule drug discovery towards novel E3 ligases for use as new mono- or bivalent degrader therapeutics.

We are tremendously excited about the opportunities that our work here has generated. Our approach to druggable pocket identification has placed us in a unique position to progress multiple novel ligases into drug discovery towards our goal of accelerating the next generation of degrader therapies into clinical development. More broadly, PhoreMost’s ability to progress a diversity of novel E3 ligases could be game changing, ultimately offering the chance to recruit the best ligase for a given target for degrader-based therapeutics.

Finally, we aim to broaden access to the PhoreMost platform again through additional partnerships. Watch this space!

Dr. Neil Torbett was speaking to Molly Campbell, Senior Science Writer for Technology Networks.