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In recent years, targeted protein degradation (TPD) has emerged as a promising approach to drug discovery, particularly for diseases with limited treatment options. By targeting previously "undruggable" proteins and harnessing the body’s natural protein degradation pathways, TPD has the potential to develop therapies that go beyond inhibition to actively eliminate disease-driving proteins.
To advance the development of novel degradation technologies, BPGbio has recently partnered with the University of Oxford. The five-year partnership will focus on E2-based protein degradation in oncology and central nervous system (CNS) diseases.
Technology Networks spoke with Dr. Vivek Vishnudas, BPGbio's chief technology officer and R&D site head, to learn more about the collaboration, the unique advantages of E2-based TPD and its potential to revolutionize treatment for challenging diseases.
Anna MacDonald (AM):
Senior Science Editor
Technology Networks
Anna is a senior science editor at Technology Networks. She holds a first-class honors degree in biological sciences from the University of East Anglia. Before joining Technology Networks she helped organize scientific conferences.
Could you provide an overview of TPD and its potential to address previously undruggable targets, particularly in oncology and neurology?
Chief Technology Officer and R&D Site Head
BPGbio
Dr. Vivek Vishnudas is BPGbio's chief technology officer and R&D site head. He oversees the development of experimental therapeutics from conception and drug discovery to IND filing and First-in-Human studies.
TPD is a novel strategy in small molecule drug discovery that has gained significant momentum.
In comparison to traditional pharmacological approaches like agonism and antagonism, TPD offers potentially superior therapeutic benefits by eliminating selective disease-causing proteins from cells.
This approach leverages small molecules to hijack the cell’s natural degradation processes, leading to the precise and efficient removal of disease-causing proteins.
Current degraders in the clinic harness E3 ligases to achieve degradation. Along with the conventional approaches, TPD will become a key component of the various therapeutic modalities that can be leveraged as a pipeline strategy across diverse therapeutic areas.
Oncology and neurology are mostly driven by protein dysregulation, hence removing such aberrant proteins through a unique TPD mechanism will benefit from a good therapeutic index. TPD in immunology and inflammation is not far behind and is being looked up as the next therapeutic frontier that will benefit from such differentiated approaches.
Senior Science Editor
Technology Networks
Anna is a senior science editor at Technology Networks. She holds a first-class honors degree in biological sciences from the University of East Anglia. Before joining Technology Networks she helped organize scientific conferences.
What sets BPGbio's E2-based TPD approach apart from traditional E3-based methods, and what unique advantages does it bring to drug development?
VV:
Chief Technology Officer and R&D Site Head
BPGbio
Dr. Vivek Vishnudas is BPGbio's chief technology officer and R&D site head. He oversees the development of experimental therapeutics from conception and drug discovery to IND filing and First-in-Human studies.
~90% of TPD programs utilize E3s such as cereblon (CRBN) or von Hippel-Lindau (VHL) but CRBN and VHL are known to have high susceptibility to resistance mechanisms.
In contrast, BPGbio’s TPD program focuses on targeting E2s, paving the way for the design of novel bifunctional degraders and monovalent glues. This approach has several inherent potential advantages from conventional E3-based methods, including:
- Increased efficacy: E2 enzymes are expressed at broader and higher levels, which enhances the potential for therapeutic efficacy.
- Lower risk of resistance: E2 enzymes have a lower mutation rate, reducing the likelihood of innate or developed cross-resistance.
Apo E2 enzymes have historically been considered undruggable due to their flat surfaces for protein-protein interaction. BPGbio has achieved strong and specific E2 binding by targeting a modified E2 complex (PTM E2), advancing the potential for drug design. BPGbio is developing chemical scaffolds that precisely bind to this modified E2, making the protein complex more amenable to therapeutic targeting.
A BPGbio ligand, designed for specific protein targets, binds to a unique pocket within the modified E2. Biophysical studies and high-resolution structural biology have confirmed strong, E2-specific binding for several BPGbio ligands, further highlighting the platform’s potential. BPGbio’s chemical biology and proteomics expertise have also enabled confirmation of E2 selectivity of these ligands.
Senior Science Editor
Technology Networks
Anna is a senior science editor at Technology Networks. She holds a first-class honors degree in biological sciences from the University of East Anglia. Before joining Technology Networks she helped organize scientific conferences.
Can you elaborate on BPGbio’s partnership with the University of Oxford’s Centre for Medicines Discovery, and how such collaborations accelerate innovation in developing next-generation therapeutics?
VV:
Chief Technology Officer and R&D Site Head
BPGbio
Dr. Vivek Vishnudas is BPGbio's chief technology officer and R&D site head. He oversees the development of experimental therapeutics from conception and drug discovery to IND filing and First-in-Human studies.
Our partnership with Oxford University is a five-year research collaboration focused on advancing novel TPD technologies, particularly in oncology and CNS diseases, with the goal of unlocking new therapeutic pathways for conditions with limited treatment options.
This partnership is a powerful alliance of biology-first science and cutting-edge translational research.
The collaboration builds on BPGbio’s first-in-class E2-based protein degradation program, which features a proprietary library of more than 1,000 Ro3 fragments discovered by BPGbio that are potential ligands and seed compounds to a variety of E2 targets. The collaboration will also utilize BPGbio’s proprietary ternary structures, its computational toolkit for E2 ligand design, and assays for rapidly attaining selectivity and specificity.
What the Centre for Medicines Discovery of Oxford University offers is its world-class expertise in translational research, including its groundbreaking efforts in neurological diseases such as Parkinson’s Disease.
The project team will utilize BPGbio’s proprietary NAi Interrogative Biology® Platform, which integrates patient biology with AI-driven analysis, to accelerate biomarker discovery and therapeutics development.
We are excited about the breakthroughs this collaboration can bring to the market.
Senior Science Editor
Technology Networks
Anna is a senior science editor at Technology Networks. She holds a first-class honors degree in biological sciences from the University of East Anglia. Before joining Technology Networks she helped organize scientific conferences.
What are the key challenges BPGbio faces in progressing E2-based protein degradation therapies from preclinical research to clinical application, and how is the company addressing them?
VV:
Chief Technology Officer and R&D Site Head
BPGbio
Dr. Vivek Vishnudas is BPGbio's chief technology officer and R&D site head. He oversees the development of experimental therapeutics from conception and drug discovery to IND filing and First-in-Human studies.
Being the first to make the long considered challenging to modulate E2s druggable is very exciting, and we are very pleased with the positive feedback we have received so far from potential pharma partners as they look for new and better ways to develop small molecule therapeutics.
We have seen that E2 is potentially more effective than E3s, and we are conducting extensive research to ensure that the E2-based degraders are as efficient or more efficient compared to E3-based degraders, so we can de-risk this groundbreaking program. We do this by focusing on rapid and sustainable degradation of targets, as well as adopting cutting-edge chemical biology and proteomics approaches that will define unique clinically relevant targets that will allow for widespread industry adoption. We are paving a differentiated path to TPD, and I firmly believe that our world-class science team has the skill set and expertise to push the E2 program forward.
When it comes to adoption of this new unconventional program, we are observing an uptick in the number of peer-reviewed journal articles related to E2-based protein degradation.1–3 This is a very positive development for the E2 TPD area of research and these findings reinforce our differentiated approach.
BPGbio is advancing E2-based TPD by designing several CRBN-independent, orally available degraders with nanomolar potency and robust degradation profiles. These developments demonstrate the potential for E2-based therapeutics in both oncology and neurology. Our E2-based lead molecules are being developed for a range of protein targets linked to various cancers, particularly where CRBN dysregulation may lead to acquired resistance against CRBN / E3-based degraders.
Senior Science Editor
Technology Networks
Anna is a senior science editor at Technology Networks. She holds a first-class honors degree in biological sciences from the University of East Anglia. Before joining Technology Networks she helped organize scientific conferences.
How do you see the field of TPD evolving over the next five years, and what breakthroughs or trends are likely to shape its future?
VV:
Chief Technology Officer and R&D Site Head
BPGbio
Dr. Vivek Vishnudas is BPGbio's chief technology officer and R&D site head. He oversees the development of experimental therapeutics from conception and drug discovery to IND filing and First-in-Human studies.
Given E3’s high resistance susceptibility, and with BPGbio leading the E2 field, and more research on pathways to E2, I believe the TPD field will be more diversified with a large number of E2 programs in five years.
BPGbio will continue to lead the E2-based TPD field with breakthrough discoveries and at least one drug candidate in clinical trials. Needless to say, E2 is a super exciting field and we appreciate this opportunity to discuss our E2 program with the industry.
References:
1. Forte N, Dovala D, Hesse MJ, et al. Targeted protein degradation through E2 recruitment. bioRxiv. 2022. doi: 10.1101/2022.12.19.520812
2. Poirson J, Cho H, Dhillon A, et al. Proteome-scale discovery of protein degradation and stabilization effectors. Nature. 2024;628(8009):878-886. doi: 10.1038/s41586-024-07224-3
3. Taylor JD, Barrett N, Martinez Cuesta S, et al. Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes. Commun Biol. 2024;7(1):1-17. doi: 10.1038/s42003-024-06803-4
