By Dr Neil Taylor
Like many professionals in the drug discovery and computational chemistry space, I’ve been following the PROTAC space with great interest. Targeted protein degradation is one of the most intellectually exciting developments in modern drug discovery, and it deserves the attention it’s getting. At the same time, it’s worth being honest about where the technology really sits today, and why for many organisations, waiting before committing to a full implementation may be the most strategic choice.
What makes PROTACs in drug discovery so compelling is their mechanism. These bifunctional molecules hijack the cell’s natural protein degradation machinery, eliminating target proteins rather than merely inhibiting their activity. The implications are significant: lower effective dosing, access to previously undruggable targets such as transcription factors, and potential ways to overcome resistance mechanisms that limit traditional inhibitors.
It’s easy to see why the field has attracted so much interest. The underlying science is elegant, and the therapeutic possibilities are genuinely transformative.
The practical hurdles, however, are substantial. PROTAC molecules typically exceed 1000 daltons, placing them well outside traditional drug-like space. That creates immediate challenges around cell permeability, oral bioavailability and pharmacokinetics. While some PROTACs have exceeded expectations, predicting which designs will succeed remains frustratingly unreliable.
The design problem itself is even more complex. You are not simply optimising binding to a single target. You are engineering a three-way interaction between the target protein, an E3 ligase and the proteasome. The resulting structure–activity relationships are often non-intuitive, and small changes can have disproportionate effects. Many teams have experienced months of work undone by a minor linker modification that completely reverses degradation activity.
“Successful PROTAC programmes depend on more than chemistry. They require enterprise-level protein structure data, specialised assays, and teams equipped to handle non-intuitive design outcomes.”
This is where a more honest conversation is needed. Most drug discovery teams are not yet equipped to run PROTAC programmes effectively.
Synthesising PROTACs demands advanced medicinal chemistry capabilities. Each molecule combines two complex binding moieties connected by a carefully designed linker, creating vast combinatorial space. Screening these compounds requires specialised assays to assess ternary complex formation, degradation kinetics and hook effects. Many laboratories simply do not have this infrastructure.
Equally important is data readiness. Successful PROTAC design depends on a deep understanding of target and off-target protein shape, charge distribution and conformational flexibility. That requires enterprise-level protein structure data resources, where all relevant structural data is readily accessible, well organised and continuously curated. Tools such as DesertSci’s Proasis exist precisely to support this kind of structure-based drug design, providing integrated access to protein structures and contextual data across drug discovery workflows. Without that foundation, PROTAC optimisation becomes guesswork.
Biology adds further uncertainty. The tissue-specific expression of E3 ligases can derail otherwise promising programmes. A PROTAC may perform well in vitro but fail in vivo because the required ligase is not expressed where it matters. This is not a flaw in the concept and may eventually enable selectivity, but it adds another layer of complexity that teams must be prepared to manage.
For well-funded pharmaceutical organisations with deep medicinal chemistry expertise and the patience for long-term investment, PROTACs may be a sensible strategic bet. Several candidates have already entered clinical trials, with encouraging early data.
For academic laboratories with limited chemistry bandwidth, smaller biotechs managing burn rate, or teams without specialist expertise across chemistry, structural biology and degradation biology, the calculus is different. In many cases, more tractable modalities may offer a faster and more reliable path to impact today.
This is not an argument against PROTACs. It is an argument about timing and readiness.
As the field matures, we will see better design tools, improved understanding of ternary complex formation and expanded ligand libraries. Over time, the technology will become more accessible. The most successful drug discovery organisations tend to share a common discipline: they match their ambitions to their capabilities. They ask difficult questions about team expertise, enterprise-level infrastructure and financial runway. They also ask whether existing approaches could achieve the same therapeutic goals more efficiently.
For PROTACs, a watch-and-learn strategy is often the most prudent move. Monitor clinical progress closely. Pay attention to which target classes show genuine traction and which continue to struggle. Build relationships with academic collaborators who understand the practical realities, not just proof-of-concept success. Where appropriate, consider strategic partnerships before investing heavily in in-house capabilities. Many CROs and specialised biotechs now offer PROTAC design and synthesis services, allowing teams to explore the modality without committing to full infrastructure build-out.
Innovation does not always reward the first mover. Sometimes it rewards the teams that wait, learn and enter the field with the right capabilities at the right moment.
Let’s continue to celebrate the science behind PROTACs, while staying realistic about the challenges of implementation. Supporting the pioneers and validating the organisations that choose patience are not mutually exclusive. In drug discovery, timing is often as important as ingenuity.
What are PROTACs in drug discovery?
PROTACs (proteolysis targeting chimeras) are bifunctional molecules that induce the degradation of target proteins by recruiting the cell’s ubiquitin–proteasome system, rather than simply inhibiting protein function.
Why are PROTACs considered promising?
PROTACs offer the potential to access previously undruggable targets, reduce required dosing, and overcome resistance mechanisms seen with traditional inhibitors. Their ability to remove proteins entirely has opened new therapeutic possibilities.
What makes PROTAC drug design difficult?
PROTACs are typically large, complex molecules with challenging pharmacokinetic properties. Designing effective ternary complexes between the target, an E3 ligase and the proteasome is often non-intuitive, and small design changes can dramatically alter activity.
Are PROTACs ready for widespread use?
While several PROTACs have entered clinical trials, the approach remains resource-intensive. Many organisations lack the chemistry, biological expertise and enterprise-level protein structure data infrastructure needed to run PROTAC programmes efficiently.
Or, if you’d like to arrange a demonstration of DesertSci’s Proasis, please get in touch with our team.
