Proteolysis-targeting chimeras (PROTACs) have emerged as a promising therapeutic modality for targeted protein degradation. Rather than inhibiting disease-causing proteins, PROTACs harness the cell’s natural protein degradation machinery to selectively eliminate them, opening new opportunities for previously undruggable targets. Several oral PROTACs have now entered clinical development, demonstrating that oral targeted protein degradation is possible. However, achieving reliable oral bioavailability remains one of the field’s greatest challenges.
Why are PROTACs difficult to deliver orally?
Most PROTACs occupy the beyond Rule-of-Five (bRo5) chemical space, where conventional principles of oral drug design no longer reliably apply. Their high molecular weight, large polar surface area and molecular flexibility collectively create significant barriers to oral absorption by limiting membrane permeability and often reducing aqueous solubility. Although clinical candidates such as bavdegalutamide (ARV-110) and vepdegestrant (ARV-471) demonstrate that oral delivery is achievable, developing PROTACs with predictable oral exposure remains a major challenge.
Beyond Molecular Design
Over the past decade, medicinal chemistry has made significant progress through optimisation of linker architecture, molecular conformation and physicochemical properties. The concept of chameleonicity, whereby molecules adopt compact conformations that temporarily reduce exposed polarity, has become an important framework for understanding how some PROTACs achieve oral exposure.
However, optimising molecular design alone is not sufficient to achieve reliable oral bioavailability. A molecule must first dissolve in gastrointestinal fluids before it can cross the intestinal membrane. For many PROTACs, poor aqueous solubility limits the concentration of dissolved drug available for absorption, making dissolution an equally important determinant of oral exposure.
Why formulation deserves more attention
Recent reviews increasingly recognise formulation as a key component of successful oral PROTAC development. Approaches including amorphous solid dispersions, lipid-based systems and nanoparticle formulations are being explored to address the biopharmaceutical challenges associated with poorly soluble bRo5 molecules. Rather than serving as a late-stage rescue strategy, pharmaceutical formulation is increasingly viewed as a complementary discipline alongside medicinal chemistry.
For compounds that combine poor solubility with limited permeability, a profile characteristic of many PROTACs, integrating formulation early in development may improve oral exposure by addressing dissolution and solubility limitations alongside molecular design.
Future Perspectives
The first generation of oral PROTACs has demonstrated that targeted protein degradation can move beyond intravenous administration. The next challenge is making oral delivery predictable.
Achieving this will require a multidisciplinary approach that combines medicinal chemistry with formulation from the earliest stages of development. At SeraNovo, we believe formulation should be viewed as an integral part of solving oral drug delivery challenges. NanoGlass™ formulations are designed to generate amorphous API nanoparticles in situ, creating a colloidal reservoir of drug within the gastrointestinal environment. As dissolved API is absorbed, this reservoir continuously replenishes the solubilised fraction, helping maintain elevated apparent solubility and the concentration gradient that drives absorption.
This mechanism links solubility enhancement, rapid dissolution, and permeability enhancement, thus NanoGlass™ is designed to maximise total oral exposure, illustrating how formulation science can improve oral exposure for challenging bRo5 molecules. As the field continues to evolve, the future of oral PROTACs will likely depend on the successful integration of both chemistry and formulation.
