Chemical Proximity as the Next Frontier in Drug Discovery From Protein Degradation to a Broader Proximity Toolbox 
 
The field of drug discovery is undergoing a profound transformation. Where traditional pharmacology has long focused on inhibiting enzymes or blocking receptors, a new generation of therapies is emerging that instead reprograms protein behavior through proximity. Chemical induced proximity (CIP)—a growing umbrella that includes protein degradation, molecular glues, and non-degrading proximity inducers—is reshaping how scientists think about target engagement, selectivity, resistance, and therapeutic durability. 
 
These themes took center stage in the Thought Leader webinar Chemical Proximity as the Next Frontier in Drug Discovery, hosted by Cerlin Roberts, CEO of Oxford Global. The session brought together leading academic and industry experts to explore how proximity-based strategies are redefining the drug discovery landscape and expanding what is considered druggable. 
 
From Concept to Clinic: The Maturation of Targeted Protein Degradation 
 
Opening the discussion, Professor Zoran Rankovic, Director of the Centre for Protein Degradation at The Institute of Cancer Research (ICR), reflected on the remarkable progress of targeted protein degradation (TPD) over the past decade.
 
Only a few years ago, the field was still grappling with foundational questions: could PROTACs ever be orally bioavailable? Could large, heterobifunctional molecules behave like real drugs? Today, those doubts have largely been put to rest. More than 40 degrader programs have entered clinical trials, the majority of them orally bioavailable, and the field has learned to operate effectively in the beyond-Rule-of-Five chemical space. 
 
At ICR, this maturation is reflected in the structure and priorities of the Centre of Protein Degradation. The centre runs three complementary research programs: PROTACs, molecular glue degraders, and the discovery and exploitation of novel E3 ubiquitin ligases. Notably, around half of CPD’s resources are now devoted to molecular glues, underscoring a growing belief that glues may ultimately unlock the largest fraction of currently “undruggable” biology. 
 
Unlike PROTACs, molecular glues do not require a defined binding pocket on the target protein. Instead, they stabilize new protein–protein interactions—often between a target and an E3 ligase—creating emergent interfaces that drive selective degradation. This makes them particularly attractive for transcription factors, scaffolding proteins, and other targets that have historically resisted small-molecule approaches. 
 
Data, Discovery, and the Promise of AI-Enabled Molecular Glue Design 
 
Despite their promise, molecular glues remain challenging to discover and optimize. Whereas PROTACs can often be designed rationally once suitable ligands are identified, glue discovery has traditionally relied on screening and serendipity. 
 
Professor Rankovic highlighted how this paradigm is beginning to shift. Through collaboration with Neosphere, CPD has adopted a high-throughput proteomics platform capable of profiling thousands of compounds across the proteome. Early results have been transformative, revealing that the cereblon substrate landscape is far broader than previously appreciated and uncovering entirely new degron motifs. 
 
Building on these insights, CPD designed a next-generation molecular glue library comprising thousands of compounds, now midway through screening. The resulting datasets—linking compound structure, ternary complex formation, degradation profiles, and downstream biology—are unprecedented in both scale and quality. 
 
The longer-term ambition is to address one of the field’s most significant bottlenecks: predictive design. By integrating deep proteomics, mutational analysis, and structural data (including X-ray and cryo-EM ternary complex structures) into machine-learning models, CPD aims to move molecular glue discovery from chance-driven screening toward rational, prospective design. While still a formidable challenge, this data-centric approach is widely seen as essential for the next phase of the field. 
 
Beyond Degradation: Non-Degrading Chemical Inducers of Proximity 
 
While protein degradation has captured much of the spotlight, it is not always the optimal solution. Dr. Rick Ewing, Vice President and Head of Chemistry at Rapafusyn Research and Development, presented a complementary perspective centered on non-degrading chemical inducers of proximity. 
 
Rapafusyn’s platform builds on the legacy of rapamycin—one of the earliest and most successful examples of a chemical inducer of proximity. Rapamycin and related natural products act by forming ternary complexes that modulate protein function rather than eliminating the target altogether. Despite their synthetic complexity, these compounds have given rise to multiple marketed drugs that continue to deliver substantial clinical and commercial impact decades after their discovery. 
 
Rapafusyn is extending this paradigm through modular, macrocyclic platforms inspired by rapamycin chemistry. By combining DNA-encoded library screening with structural biology, the company has identified new disease-relevant targets and validated unique ternary complex binding modes, including examples where proximity inducers directly disrupt pathogenic protein–protein interactions. 
 
Dr. Ewing emphasized that non-degrading molecular glues occupy a critical niche. In some disease contexts, complete removal of a protein may lead to unacceptable toxicity or loss of essential physiological function. In others, precise modulation—achieved by locking proteins into inactive or mislocalized complexes—may provide the desired therapeutic benefit with improved safety. 
 
From this perspective, chemical induced proximity is not a single modality, but a spectrum of approaches ranging from catalytic degradation to stable, inhibitory protein complexes. 
 
Choosing the Right Modality: A Biology-First Strategy 
 
A recurring theme throughout the panel discussion was the importance of matching modality to biology rather than defaulting to any single approach. 
 
Dr. Danette Daniels, Vice President of the Protein Degrader Platform at Foghorn Therapeutics, described how her team evaluates whether inhibition, degradation, or another proximity-based strategy is best suited for a given target. Enzymatic proteins may be amenable to inhibition, but non-enzymatic scaffolding proteins or chromatin regulators often require more disruptive strategies to fully disable their function. 
 
Foghorn’s work on the closely related chromatin regulators CBP and EP300 illustrates this principle. Traditional inhibitors struggle to distinguish between these highly homologous proteins, limiting selectivity. By applying degradation, Foghorn was able to introduce selectivity at the level of protein removal, unlocking distinct biological and phenotypic outcomes that inhibition alone could not achieve. 
 
Similarly, the company’s success in targeting ARID1B—a protein long considered undruggable—demonstrates how bifunctional and proximity-based approaches can overcome limitations predicted by conventional druggability models. 
 
Induced Proximity for Transcriptional Rewiring and Epigenetic Control 
 
Beyond degradation, induced proximity is increasingly being explored as a way to reprogram transcriptional and epigenetic networks. By re-localizing chromatin regulators or altering the composition of multiprotein complexes, proximity inducers can reshape gene expression programs in highly specific ways. 
 
Dr. Daniels noted that while the potential is substantial, these approaches raise important mechanistic questions. Directionality on chromatin, unintended redistribution of regulatory complexes, and the balance between re-localization and sequestration all remain active areas of investigation. Nevertheless, early examples suggest that proximity-based transcriptional rewiring could open entirely new therapeutic avenues. 
 
Covalency, Safety, and Translational Complexity 
 
As proximity modalities proliferate, so do their translational considerations. Covalent strategies, in particular, are attracting renewed interest across both degrading and non-degrading approaches. Covalent engagement of E3 ligases or proximity partners can enhance potency and durability but also raises questions around recycling, selectivity, and long-term safety. 
 
Professor Rankovic underscored that TPD safety is inherently more complex than classical inhibition. Proximity-based drugs modulate not only the target protein but also the recruited ligase and its endogenous substrate network. Species-specific differences in ligase biology—historically exemplified by thalidomide—remain a critical consideration in preclinical development. 
 
RIPTACs and “Hold-and-Kill” Pharmacology 
 
Adding another dimension to the proximity landscape, Kyle Eastman, Vice President and Head of Chemistry at Halda Therapeutics, described the company’s RIPTAC (Regulated Induced Proximity Targeting Chimera) platform. 
 
RIPTACs are heterobifunctional molecules, but unlike PROTACs, they do not rely on ubiquitination and degradation. Instead, they operate through a “hold-and-kill” mechanism, forming exceptionally stable ternary complexes between a target protein and a pan-essential protein. Importantly, the essential-protein ligand binds weakly in isolation, ensuring that pharmacology is triggered only in cells where the target protein is present at sufficiently high levels. 
 
This mechanism offers distinct advantages in resistance settings. In prostate cancer, for example, RIPTACs can exploit the presence of full-length androgen receptor to drive pharmacology even when disease progression is driven by splice variants that evade conventional inhibitors and degraders. 
 
From a medicinal chemistry standpoint, Dr. Eastman emphasized that proximity drugs still obey many of the same principles as traditional small molecules. Oral bioavailability remains achievable, but only through careful management of hydrogen bonding, linker rigidity, polarity, and molecular weight. Novel pharmacology does not eliminate the need for disciplined chemical design. 
 
The Road Ahead: Toward Precision Proximity Medicine 
As the webinar concluded, a clear message emerged. Protein degradation has evolved from an experimental concept into a validated therapeutic strategy—but it represents only one part of a rapidly expanding proximity ecosystem. 
 
Future progress will depend on: 
  • Expanding beyond a small set of well-characterized E3 ligases 
  • Applying a biology-first framework to modality selection 
  • Generating high-quality datasets to enable predictive modelling of ternary complex cooperativity 
  • Extending proximity strategies into new cellular compartments, including extracellular and membrane proteins 
  • Integrating proximity inducers with other modalities, such as antibody–degrader conjugates 
Chemical induced proximity is not replacing traditional drug discovery—it is augmenting it. By enabling precise control over protein fate, function, and localization, proximity-based approaches are opening therapeutic opportunities that were once considered unreachable. 
 
The next frontier will not be defined by a single technology, but by how intelligently these tools are matched to biology to deliver meaningful benefit to patients.