Following the recent introduction of our new GlueSEEKER platform, we interviewed Dr Jia Lu, Principal Scientist in the Target Discovery Team.
In this latest blog, Jia discusses his experiences working with mini proteins, the challenges associated with the development of new molecular glue degraders (MGDs), and shared updates on PhoreMost’s internal programmes.
Can you tell us a bit more about your background and career to-date?
My academic background is virology and molecular biology; I obtained a BSc in biochemistry from the Chinese University of Hong Kong, before moving to the UK to complete a Master’s degree at Imperial College London and PhD at the University of Cambridge. Here, I worked with Professor Ian Goodfellow to develop biochemical and proteomic assays to characterise virus-host cell interactions for the rational attenuation of noroviruses. I then joined Dr Martin Turner’s lab at the Babraham Institute, as a postdoctoral research scientist, and worked on characterising novel micropeptides during lymphocyte activation, which inspired my interest in mini proteins and their potential in drug discovery. Outside of work I enjoy running, table tennis, gardening and cooking.
When did you join PhoreMost, and what attracted you to the company?
I joined PhoreMost in 2021 following my post-doc work at Babraham. I learned about the SITESEEKER platform and proprietary PROTEINi technology, a mini protein-based high-throughput target discovery approach, and decided to join the Target Discovery team.
What makes PhoreMost’s approach to drug discovery unique?
Abberant protein-protein interactions (PPIs) are often associated with diseases such as cancers, and are increasingly targeted for novel therapeutic development. However, current small molecule screening tools are not optimised to target PPIs.
The SITESEEKER technology uses PROTEINi, genetically engineered and encoded mini proteins, as a proxy to survey the target PPIs and identify relevant drug targets and novel druggable sites. Combining recent advances in next generation sequencing (NGS), functional genomics, and AI-assisted computational biology, this approach enables PhoreMost to unlock the undruggable genome and accelerate drug discovery processes.
PhoreMost recently introduced its GlueSEEKER platform to enable to discovery of novel molecular glue degraders – what potential does this hold for new drug discovery and development?
GlueSEEKER started as one of our ‘Friday afternoon’ projects, initially designed to test if we can engineer PROTEINi within a target protein. Very quickly we realised this represented a unique opportunity to design and evaluate de novo PPIs, and applying it to targeted protein degradation (TPD) would enable us to tackle the challenges associated with novel MGD discovery.
What are the challenges associated with the development of new MGDs?
The two major modalities of the TPD field are Proteolysis Targeting Chimeras (PROTACs) and MGDs. Compared to PROTACs, MGDs have more favourable pharmacological properties, but to date all MGDs have been discovered by serendipity. Therefore, the first challenge is the development of systematic tools to discover novel MGDs. MGDs promote protein-protein interactions between E3 ligases and degradation targets, i.e. proteins of interest (POIs) or neosubstrates. The explosive application of AI in computational biology has predicted more protein structures than ever, but generative models to predict previously unrealised PPIs are still lacking.These challenges render new MGD discovery like searching for a needle in a haystack.
How is GlueSEEKER helping researchers to overcome these challenges?
MGDs work by inducing protein-protein interactions, and nothing does that better than proteins themselves. GlueSEEKER uses MG-PROTEINi to modify novel E3 ligase-POI interfaces, and evaluate the efficacy with biologically relevant readout, e.g. degradation assays. This can be used to systematically screen hundreds of thousands of MG-PROTEINi to understand the chemical space required to induce POI degradation and guide new MGD design.
Moreover, MG-PROTEINi can be engineered into any E3 ligase and POI pair, with relatively limited requirements of existing structural information, making GlueSEEKER an incredibly powerful tool to discover beyond cereblon-based MGDs.
How does GLUESEEKER expand on PhoreMost’s SITESEEKER platform?
Both SITESEEKER and GlueSEEKER use PROTEINi to accelerate drug discovery. SITESEEKER is designed to uncover global novel drug targets. As the platform evolves, we are able to incorporate more technical and computational knowledge into the development of GlueSEEKER, which excels at providing high resolution information of local PPIs de novo.
What exciting developments are you currently working on at PhoreMost?
There is a lot of fantastic work going on at PhoreMost. Our internal programs are entirely focused on TPD – both heterobifunctional degraders and new MGDs. We are applying our novel E3 ligase chemistry to develop heterobifunctional degraders for high-value oncology and inflammation targets and are particularly excited about our lead ligase program, which we have shown to work through a cancer-selective mechanism.
As well as our internal TPD programs, we also use our core SITESEEKER platform to partner with pharma partners. As the platform can be used across all therapeutic areas, we have many great collaborations with industry-leading partners such as Boehringer Ingelheim and Roche. The bredth of potential applications of our technology is enormous, and is a big part of what makes PhoreMost such an exciting company.