Unlocking the Promise of Protein Degraders: Molecular Glues, PROTACs, and the Path Forward

OG’s Thought Leadership webinar, “Unlocking the Promise of Protein Degraders: Molecular Glues, PROTACs, and the Path Forward.” With targeted protein degradation (TPD) now one of the most dynamic frontiers in drug discovery, this session brought together leaders from across pharma and biotechnology to explore how molecular glues and PROTACs are reshaping what’s possible in therapeutic development.

The one-hour virtual event, hosted on 12th November (1:30–2:30 PM BST / 8:30–9:30 AM EST), opened with a featured interview and presentation from Stefan Schiesser, Director of Medicinal Chemistry at AstraZeneca, followed by a panel discussion moderated by Stefan and supported by three experts at the leading edge of degrader innovation:

  • Benedict Cross, CTO & Head of Platform, Phoremost
  • Marta Carrara, Associate Director of Target Discovery & Validation, Amphista
  • Adam Yip, Director of Drug Discovery, TeraryTx

Together, they mapped the state of the field today—what’s working, what’s still hard, and what the next generation of technologies might unlock.

A New Therapeutic Logic: Degradation Over Inhibition

Stefan’s opening presentation set the tone for the session by emphasizing the conceptual shift that protein degraders represent. For decades, medicinal chemistry has largely focused on inhibiting proteins—blocking an active site, disrupting a pathway, reducing function. Protein degradation flips that model. Instead of suppressing protein activity, degraders harness the cell’s own machinery to remove the protein entirely.

This is far more than a technical nuance. Degradation allows drug hunters to engage targets that have resisted inhibition-based approaches, including proteins lacking clear binding pockets or operating via scaffolding or regulatory roles. It also introduces the tantalizing possibility of more durable responses—since the protein itself is cleared, not merely bound temporarily by a drug.

Within targeted protein degradation, two modalities have risen to prominence:

  • Molecular glues, which induce or stabilize interactions between a protein of interest and an E3 ligase, leading to ubiquitination and degradation.
  • PROTACs, bifunctional molecules that physically link a target to a ligase, forming a ternary complex that triggers degradation.

Stefan highlighted that both approaches aim for the same endpoint but follow very different discovery and development paths, creating an exciting but complex translational landscape.

Panel Discussion: Accelerating the Future of Molecular Glues

Following Stefan’s presentation, the conversation moved into a fast-paced panel discussion titled “Accelerating the Future of Molecular Glues: Discovery, Development, and Translational Horizons.” While PROTACs have dominated much of the public narrative around TPD, the panel focused on molecular glues as a rapidly maturing and uniquely powerful modality.

Rational Discovery: Moving Beyond Serendipity

One of the core tensions in molecular glue development is that the field was built on phenotypic discovery. Some of the most successful glues emerged through screening compounds in cells and observing unexpected degradation effects. The biology came first; the mechanism followed.

But as the field scales, the appetite for rational design is growing. Panelists discussed how discovery is evolving toward a more systematic model centered on:

  • Target selection
  • Ligase compatibility
  • Ternary complex formation
  • Degradation efficiency and selectivity

A key point: molecular glues don’t work simply because they bind a protein. They work because they re-write protein–protein interaction rules, prompting a ligase to recognize a target it wouldn’t normally degrade. This makes them difficult to design predictively—but also uniquely versatile when successful.

The panel explored the trade-off between discovery strategies:

  • Phenotypic screens remain valuable for uncovering unexpected glues and new biology.
  • Target-centred screens can accelerate optimization once a mechanistic path is clearer.

Rather than treating these as opposing routes, the panel agreed that the future likely lies in hybrid discovery models that combine phenotypic breadth with target-specific clarity.

Expanding the Toolbox: Beyond CRBN

A major bottleneck in glue discovery is the narrowness of the ligase toolbox. Historically, much of molecular glue success has relied on CRBN (cereblon) and a small handful of other ligases. While this has produced landmark drugs and strong pipelines, it also limits how broadly molecular glues can be applied across targets and tissues.

Panelists spoke about active efforts to expand beyond CRBN-based glues, including:

  • identifying new E3 ligases with amenable binding sites
  • building chemistry that can engage them
  • profiling ligase biology to understand where and when degradation may be feasible

This diversification matters because different ligases carry different substrate preferences, expression patterns, and cellular rules. Broadening ligase access will expand the universe of glueable targets and may unlock degraders in new disease contexts.

Molecular Glues vs. PROTACs: A Strategic Comparison

The panel also discussed the complementary roles of molecular glues and PROTACs. While both rely on ternary complex formation, their properties differ in ways that shape clinical viability.

Molecular glues

  • typically smaller and more drug-like
  • often easier to formulate and deliver orally
  • biologically powerful but harder to discover rationally

PROTACs

  • more modular and designable
  • discovery paths can be more straightforward
  • often live in bRo5 (beyond rule-of-five) chemical space, raising oral exposure and distribution challenges

The conclusion wasn’t that one modality is superior, but that each brings distinct advantages depending on target biology and development goals. A mature TPD strategy needs both options.

Enabling Technologies & AI: Turning Complexity Into Predictability

Few areas of drug discovery are as structurally and computationally hungry as targeted protein degradation. The panel underscored that glue programs increasingly depend on deep structural insight—specifically, understanding how ligase, glue, and target align in space to form stable ternary complexes.

Leveraging ternary complex structures enables:

  • rational optimization of glue chemistry
  • prediction of degradation selectivity
  • early flagging of liabilities
  • higher confidence in translation

Alongside structural biology, the panel highlighted the emerging impact of AI and machine learning. These tools are beginning to:

  • prioritize targets more likely to be glueable
  • model ternary complex stability
  • suggest chemical modifications for stronger degradation
  • interpret proteomic changes at scale

The message here was practical, not speculative: AI is becoming an integral part of degrader discovery, helping shift the field from chance findings to design-driven programs.

Emerging Frontiers: New Modalities and Translational Horizons

Finally, the panel explored where degraders may go next. One of the most notable emerging frontiers discussed was antibody–degrader conjugates. By linking degraders to antibody scaffolds, these hybrid therapies might enable targeted degradation in tissues or cell populations that small molecules struggle to access—potentially improving therapeutic windows and precision.

Clinical translation, however, remains a high-bar phase. The panel emphasized that moving glues and PROTACs into the clinic requires careful attention to:

  • degradation selectivity
  • PK/PD alignment
  • safety monitoring via proteome-wide profiling
  • clear differentiation compared to inhibitors

In other words, success in vitro is only the beginning. Translational strategy must be engineered as deliberately as chemistry.

Audience Q&A: Real-World Challenges and Competitive Futures

The Q&A segment surfaced two questions that captured both the technical and strategic stakes of the field.

bRo5 Oral PROTAC Development: Strategies and Pitfalls

PROTACs often exceed classical drug-likeness constraints, complicating oral exposure. The panel discussed the need for tailored optimization logic in bRo5 space—balancing size, permeability, polarity, and stability without compromising ternary complex formation. Rather than avoiding bRo5 territory, developers are increasingly learning how to engineer within it effectively.

The Competitive Landscape: What Happens Next?

Asked how the TPD landscape may evolve over the next five years, the panel anticipated all three dynamics in parallel:

  • more partnerships between biotech innovators and large pharma
  • selective consolidation around platforms, ligases, and clinical assets
  • continued diversification into new ligases, modalities, and disease areas

The shared view: targeted protein degradation is still early in its growth curve, and competition will intensify as both tools and pipelines expand.

Closing Thoughts

The overall takeaway was clear: targeted protein degradation is entering a new era.

The early phase proved degraders could work. The next phase will make them scalable, predictable, and clinic-ready—through rational discovery, a broader ligase toolbox, enabling technologies, and more integrated development approaches.

For anyone working in discovery, translational research, or strategic platform development, this field represents not just a new modality, but a new way to think about drugging biology. Molecular glues and PROTACs are expanding the definition of what’s “druggable”—and the pathway forward looks richer, more diverse, and more clinically ambitious than ever.