Reaching for Riper Targets: Chemical Neomorphs and Expanding the Druggable Cancer Proteome

While small-molecule drugs underpin most modern medicines, their scope has long been considered restricted, with approximately 80% of the human proteome historically regarded as inaccessible to classical small-molecule approaches. Chemical biologist and small-molecule developer Dr. Georg E. Winter, life science director at the Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences (AITHYRA), has previously described this accessibility challenge as standing beneath a tree heavy with ripe fruit: numerous tempting biological targets in plain sight, but frustratingly out of reach.

As research shifts toward increasingly complex disease targets—particularly in oncology—this limitation has become a key bottleneck in drug discovery. Winter has spent the last decade challenging this stance by rethinking how small molecules interact with biology. Drawing inspiration from naturally occurring compounds that act through close association and repeated exposure, Winter’s research focuses on designing chemical neomorphs capable of rewiring cellular machinery.

“Our goal is to develop small molecules that can reprogram cancer cells… traditional drugs frequently inhibit mutated or overexpressed proteins in cancers. But many disease-causing proteins remain elusive,” cautioned Winter.

In this interview, Winter explains how proximity‑inducing small molecules drive targeted protein degradation, why this approach differs from classical inhibition, and how reprogramming protein fate—rather than blocking activity—could unlock new therapeutic strategies for cancer and beyond.

Defining chemical neomorphs and understanding their therapeutic potential

Can you describe what a chemical neomorph is and share an example? How can this concept be applied to develop new therapeutic strategies?

Chemical neomorphs challenge the traditional idea that small molecules function exclusively by inhibiting protein activity. Instead, these clever little molecules provide proteins with new behaviors by altering how they interact with other cellular components. Winter describes chemical neomorphs as compounds that expand a protein’s functional repertoire, effectively rewiring biological pathways rather than switching them off.

Small-molecule degraders such as PROTACs or molecular glues are considered chemical neomorphs, as they redirect the activity of E3 ubiquitin ligases. These ligases typically recognize a limited set of substrates, but chemical neomorphs can prompt them to ubiquitinate entirely new targets, flagging them for destruction by the proteasome.

As Winter explained, these compounds “reprogram an E3 ubiquitin ligase to ubiquitinate a target protein that the ligase would typically not recognize”.

This mechanism opens new therapeutic possibilities by bypassing the need to inhibit difficult targets directly. Rather than requiring a high‑affinity binding pocket, chemical neomorphs exploit proximity. Think of them as molecular matchmakers—bringing together proteins that would otherwise never meet.

“Chemical neomorphs are small molecules that endow target proteins with new functions or expand their functional scope.” — Georg E. Winter, PhD.

Core concepts in chemical neomorph design:

• Chemical neomorphs rewire protein behavior rather than inhibiting activity directly
• Degrader molecules exemplify how bringing proteins together can redirect the cell’s machinery
• This strategy reduces the need for traditional drug-binding sites
• Functional protein reprogramming broadens the therapeutic landscape

Why targeted protein degradation goes beyond traditional drug design

Your AACR presentation highlights targeted protein degradation as a therapeutic approach. How does this differ from traditional drugs, and what makes it particularly promising for cancer therapy?

Conventional small-molecule drugs usually work by binding to a specific target and blocking it, inhibiting a specific enzymatic or signaling function. Targeted protein degradation (TPD), by contrast, “can completely eliminate a target and hence disrupts all associated functions.”

The complete removal of the protein target translates into a deeper biological intervention, particularly relevant in cancer, where redundancy and adaptive resistance often undermine partial inhibition. By forcing cancer cells to resynthesize degraded proteins, degraders introduce what Winter described as a “pharmacokinetic–pharmacodynamic disconnect.” Even transient exposure to the drug can result in sustained biological effects.

Selectivity further strengthens the appeal of TPD. Although counterintuitive, degraders can achieve high specificity through the formation of ternary complexes, meaning only certain protein–ligase pairings are effectively engaged. This combination of depth, durability, and selectivity has led to growing enthusiasm for degraders as next‑generation cancer therapeutics.

Advantages of TPD in cancer research:

• Complete target removal enables deeper disruption than inhibition
• Sustained effects arise even after drug clearance
• TPD can achieve high selectivity through induced proximity
• Coopting E3 ligases with restricted expression can potentially allow for cell- or tissue-selective degradation

PROTACs and molecular glues: two routes to protein elimination

Different types of protein degraders exist, for example, PROTACs and molecular glues. Could you briefly explain the difference and what each approach is best suited for?

Although PROTACs and molecular glues share the same goal—protein degradation—their molecular architectures differ substantially. “PROTACs have a bifunctional design, leveraging one ligand to bind to the target and another ligand to bind to the E3 ubiquitin ligase,” explained Winter. He noted that this makes them comparatively straightforward to design when suitable binders for the target already exist.

However, some disease‑relevant proteins lack obvious ligandable pockets and resist conventional small‑molecule engagement. “In contrast, molecular glue degraders only bind the ligase or the target and orchestrate several protein–protein interactions to stabilize a ternary complex (i.e., target–glue–ligase). As a result, they can induce the degradation of proteins without having to bind to them in isolation,” noted Winter.

This ability to induce degradation without directly binding the target protein in isolation dramatically expands the scope of TPD. As Winter explained, molecular glues can therefore address proteins historically deemed “undruggable,” redefining what small molecules can achieve.

PROTACS and molecular glues have key differences:

• PROTACs use bifunctional designs requiring defined target binders
• Molecular glues stabilize latent protein–protein interactions
• Glues can address targets lacking classical binding pockets
• Both strategies expand the reach of TPD

Moving beyond loss‑of‑function: rewiring protein activity through proximity

Your AACR plenary alludes to the fact that the potential of these drugs extends beyond loss-of-function mechanisms. Can you tell us more?

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While TPD is often framed as a loss‑of‑function strategy, Winter argues that degradation is only one manifestation of proximity‑based control. In some disease contexts, simply eliminating a protein may not produce the most potent therapeutic effect. Instead, actively rewiring protein function through induced proximity can unlock new modes of intervention.

“For instance, it has been shown that actively rewiring the transcriptional repressor BCL6 in B-cell lymphomas leads to a more potent effect than BCL6 inhibition or degradation. Mechanistically, this can be achieved by inducing proximity to transcriptional activators or chromatin regulators,” said Winter.

This concept aligns with the group’s broader theory: that organizing medicines around proximity induction enables researchers to move beyond evolutionary constraints. Rather than blocking or removing proteins, future therapeutics may program new cellular behaviors by design.

Beyond degradation: Functional reprogramming strategies:

• Proximity induction can go beyond protein elimination
• Rewiring transcriptional regulators can enhance therapeutic impact
• Induced proximity allows active reprogramming of cellular pathways
• This approach expands the conceptual toolkit of small‑molecule drug design
  
  

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