BPGbio’s First-In-Class program utilizing the ubiquitin conjugating enzyme (E2) for targeted protein degradation (TPD)

TPD is a novel strategy in small molecule drug discovery that has gained significant momentum. Unlike traditional protein inhibition methods, TPD offers potentially superior therapeutic effects by eliminating problematic 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. Conventional degraders harness E3 ligases to achieve degradation.  Recent advancements by Poirson et al., as published in Nature, have demonstrated that E2 enzymes, once thought to be challenging to target, can be potent effectors of TPD, opening new avenues for drug discovery.

~90% of TPD programs utilize E3s such as CRBN or VHL, 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

In addition to utilizing E2s, the program features a proprietary library of >1,000 Ro3 fragments discovered by BPGbio that are potential ligands and seed compounds to a variety of E2 targets, proprietary ternary structures, a computational tool kit for E2 ligand design, and assays for rapidly attaining selectivity and specificity.

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. The specific binding affinity of this ligand to the modified E2 was validated using surface plasmon resonance (SPR). Biophysical studies and high-resolution structural biology have confirmed strong, E2-specific binding for several BPGbio ligands, further highlighting the platform’s potential.

BPGbio is at the forefront of advancing Targeted Protein Degradation (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. BPGbio’s E2-based lead molecules are being developed for a range of protein targets linked to various cancers, particularly where CRBN dysfunction may lead to acquired resistance against CRBN / E3-based degraders.

Advanced hits from BPGbio’s E2 Platform have demonstrated independence from CRBN and VHL, and are non-thalidomide-based, effectively mitigating a common toxicity risk associated with traditional approaches.

The BPGbio Protein Homeostasis program also includes E2-based molecular glue leads for Huntingtin homeostasis, with potential extension beyond Huntington’s Disease to other neurodegenerative or Poly(Q) disorders.

 

ASMS 2025 Poster – UBE2 Family TPD

SfN24 Poster – Alzheimer’s Disease Biomarker

SfN24 poster – UBE2K Huntington’s Drug Target