The oncology landscape is undergoing a fundamental transformation. For decades, cancer treatment relied on cytotoxic chemotherapies that indiscriminately attacked rapidly dividing cells. Today, we're witnessing the emergence of precision approaches that target the molecular machinery driving individual tumours. At PC&H, we believe targeted protein degradation (TPD) represents one of the most compelling investment opportunities in modern oncology.

The Promise of Targeted Protein Degradation

Traditional small molecule inhibitors work by occupying the active site of a disease-causing protein, blocking its function. However, this approach has significant limitations: it requires high drug concentrations, targets must have "druggable" binding pockets, and resistance mutations can emerge that restore protein function.

Targeted protein degradation offers an elegant solution. Rather than simply inhibiting a protein, TPD technologies hijack the cell's natural protein disposal system, the ubiquitin-proteasome pathway, to selectively eliminate disease-causing proteins entirely. According to research published in PubMed, PROTACs (Proteolysis Targeting Chimeras) form a ternary complex with a hijacked E3 ubiquitin ligase and a target protein, leading to polyubiquitination and degradation of the target.

The human proteome contains approximately 20,000 proteins, with more than 600 functionally important for various cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional pharmacology. TPD opens the door to this previously "undruggable" proteome.

Clinical Validation and Pipeline Progress

The field has rapidly matured from academic curiosity to clinical reality. PROTACs targeting approximately 50 proteins have been successfully developed, with several now in clinical trials for cancer therapy. The technology offers multiple advantages: resilience to acquired mutations, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins that were previously untouchable.

Recent clinical data has been particularly encouraging. A 2025 review in Nature Reviews Cancer notes that PROTACs are on the verge of first clinical approval, with structural and mechanistic insights combined with technological advances promising to unlock rational design of protein degraders.

Beyond PROTACs: Molecular Glues

While PROTACs have garnered significant attention, molecular glue degraders represent an equally important modality. These smaller molecules induce novel protein-protein interactions that redirect E3 ligases toward neo-substrates. The clinical success of thalidomide analogues like lenalidomide in multiple myeloma has validated this mechanism, and next-generation molecular glues are now entering clinical development.

Our Investment Thesis

We see several compelling reasons to increase our allocation to TPD-focused companies:

Expanded target space: The vast majority of the approximately 600 human E3 ligases remain unexplored, presenting enormous opportunities to develop degraders targeting oncoproteins with tissue, tumour, and subcellular selectivity.

Platform scalability: Companies with robust TPD platforms can rapidly generate degraders against new targets, creating pipeline optionality and partnership opportunities.

Resistance mitigation: Because degraders eliminate proteins rather than simply inhibiting them, they may prove more durable against resistance mechanisms that plague conventional targeted therapies.

Looking Ahead

The targeted protein degradation space is evolving rapidly. New modalities beyond molecular glue degraders and PROTACs continue to emerge, expanding the toolkit available to drug developers. We anticipate that successful cancer treatment in the future will require combinations of immunomodulatory, antiviral, and direct degradation strategies.

At PC&H, we're actively evaluating opportunities across the TPD ecosystem, from early-stage platform companies to clinical-stage assets approaching pivotal trials. The convergence of improved understanding of protein homeostasis, advances in structural biology, and sophisticated medicinal chemistry creates an unprecedented opportunity to address cancers that have long evaded effective treatment.

References (via PubMed)

  • Li X, Song Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J Hematol Oncol. 2020;13(1):50. DOI: 10.1186/s13045-020-00885-3
  • Kelm JM et al. PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy. Mol Cancer. 2023;22(1):62. DOI: 10.1186/s12943-022-01707-5
  • Dale B et al. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer. 2021;21(10):638-654. DOI: 10.1038/s41568-021-00365-x
  • Hinterndorfer M et al. Targeted protein degradation for cancer therapy. Nat Rev Cancer. 2025;25(7):493-516. DOI: 10.1038/s41568-025-00817-8
  • Adams CM et al. Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer. Cancer Discov. 2023;13(5):1210-1229. DOI: 10.1158/2159-8290.CD-22-1131