Abstract
Targeted protein degradation has become an important therapeutic approach, with proteolysis targeting chimeras (PROTACs) and molecular glue degraders progressing across multiple drug development programs.
By promoting catalytic removal of target proteins, degraders differ fundamentally from conventional small molecule inhibitors. However, the physicochemical characteristics required for protein degradation often place these molecules outside traditional small molecule property space, resulting in significant challenges for oral delivery related to size, molecular flexibility, low solubility, and limited permeability.
What are protein degraders and why are they relevant?
Protein degraders are small molecules that induce the selective removal of a target protein by hijacking the cell’s ubiquitin–proteasome system. Degraders promote physical elimination of the target protein instead of transient inhibition, potentially enabling prolonged target suppression beyond the period of drug exposure.
The most established class of degraders are PROTACs, which are heterobifunctional molecules composed of a ligand for the target protein, a ligand for an E3 ubiquitin ligase, and a linker connecting the two. By forming a ternary complex between the target and the ligase, PROTACs trigger ubiquitination and subsequent proteasomal degradation of the target protein. Molecular glue degraders represent a second major class of protein degraders and, unlike PROTACs, promote degradation by stabilizing or inducing interactions between an E3 ligase and a target protein, without requiring a bifunctional architecture.
Interest in protein degradation has grown rapidly because this approach expands the druggable proteome and offers potential advantages over conventional small molecule inhibition, including a catalytic mode of action and, in certain contexts, the ability to address resistance mechanisms associated with target inhibition. As a result, an increasing number of degrader programs are advancing into preclinical and clinical development. As these programs progress, challenges related to formulation and manufacturability have become increasingly apparent.
Why protein degraders are difficult to formulate?
1. Beyond traditional small molecule space
Most protein degraders, particularly PROTACs, fall outside traditional small molecule property space and often beyond Lipinski’s Rule of Five. Their high molecular weight, polarity, and flexibility frequently lead to low aqueous solubility and limited passive membrane permeability. These properties therefore need to be carefully addressed during formulation development.
2. Solubility–permeability trade offs
For protein degraders, solubility and permeability are often both limiting and closely linked. Strategies used to increase solubility, such as ionization, cosolvents, or solubilizing excipients, may increase the risk of precipitation when the formulation is diluted or exposed to changes in pH in the gastrointestinal tract. In addition, the pharmacological response of some degraders may not scale linearly with exposure, reflecting the complex relationship between concentration, target engagement, and degradation efficiency. As a result, achieving controlled and reproducible exposure becomes particularly important, since variability in absorption can have a strong impact on pharmacological outcome.
3. Chemical stability and excipient interactions
The structural complexity commonly observed in protein degraders can increase the likelihood of chemical stability considerations during formulation development. Degradation pathways such as hydrolysis, oxidation, and isomerization may occur under formulation relevant conditions, and interactions with excipients can further contribute to chemical degradation. These risks are particularly relevant in low dose and solution based formulations, and therefore need to be taken into account during formulation design.
Mechanism-based formulation approach for protein degraders
One formulation approach for protein degraders limited by solubility and permeability is the controlled generation and maintenance of supersaturation in the gastrointestinal tract. In NanoGlass™ formulations, the drug is administered orally as a tablet or capsule and dissolves upon exposure to gastric fluids, resulting in the formation of amorphous drug nanoparticles.
These amorphous nanoparticles maintain the drug in a supersaturated state as they transit through the gastrointestinal tract and remain physically stable under relevant conditions. They function as a reservoir that continuously replenishes the dissolved drug fraction as absorption proceeds in the small intestine. By sustaining high thermodynamic activity at the intestinal membrane, this approach supports transmembrane transport without reliance on high excipient concentrations or short lived solubilization effects.
The formulation mechanism is therefore designed to enhance apparent solubility while maintaining physical stability, addressing key challenges commonly encountered in protein degrader development.
If you are working with a protein degrader that presents bioavailability challenges, you can contact SeraNovo to discuss NanoGlass™ technology.
