Proteolysis-targeting chimeras (PROTACs) are some of the most eagerly discussed therapies in the world due to their potential to treat conditions previously thought undruggable. Their ability to degrade rather than inhibit proteins means they can better treat complex diseases such as cancers and neurodegeneration, giving them advantages over traditional small molecule drugs.
However, PROTACs pose significant challenges to researchers developing new therapies. Their poor solubility and permeability make designing, developing, and studying challenging. This difficulty is primarily due to their structure. A PROTAC molecule has three parts: a target-binding component that attaches to the protein to be degraded, an E3 ligase-binding component, and a linker that connects the two. The structure contains at least two ligands, which raises the molecular weight, leading to poor absorption and distribution.
PROTACs also have many polar chemical bonds, which increases their topological polar surface area, hindering their ability to cross cell membranes and physiological barriers. These characteristics put PROTACs at odds with Lipinski’s Rule of Five, which has long dictated which drugs can be taken orally. However, there are effective methods that manufacturers can employ to overcome these challenges.
1. Ensure proper bioanalytical testing of PROTACs
Poor solubility, which affects how a drug is absorbed, distributed, and used in the body, is a critical challenge researchers face when developing PROTACs. A drug with a lower level of solubility may guide require a higher dose to be effective and can also cause off-target effects if elimination is prolonged. Proper bioanalytical testing of PROTACs is integral to solving these solubility issues.
For example, close attention should be paid to the solubility of a PROTAC in a physiological solution at an early stage because PROTACs may be more soluble in fed-state simulated intestinal fluid. It’s also crucial to screen delivery vehicles to achieve the best drug delivery formulation possible.
Permeability is another key challenge to PROTAC development, and collecting reliable data is key to solving this issue. PROTAC molecules suffer low permeability regardless of the model used, which may lead to insufficient recovery in in vitro permeability systems.
2. Consider a prodrug strategy
A prodrug strategy, where an inactive or less active form of a drug is used to help release the active compound, can also address the solubility issue and increase oral bioavailability. In a 2020 paper published in the European Journal of Medicinal Chemistry, researchers attached a lipophilic group to the CRBN ligand of a PROTAC compound to create a prodrug. They found that this method improved bioavailability.
3. Optimize the linker structure of PROTACs
Optimizing the linker structure is one of the most effective ways to improve cellular permeability. Ensuring the right length, rigidity, and hydrophilicity of ligand-connecting linkers drastically increases the chances of success when designing PROTACs. A shorter linker helps reduce molecule weight, and hydrophobic linkers help PROTACs cross cell membranes. More flexible linkers also enjoy higher membrane penetration.
4. Reduce the molecular weight of PROTACs
Reducing the molecular weight is essential to improving the permeability and solubility of PROTACs. In addition to shortening the linkers, developers can use smaller ligands, simplify polar groups, and remove redundant groups that don’t contribute to the drug’s core goals. These changes must be balanced against any potential loss of degradation efficiency or binding affinity.
5. Experiment with new drug delivery systems
Changing PROTACs’ drug delivery systems can help overcome the development challenges. Carriers can enable rapid delivery to disease sites and reduce adverse effects.
Nanomaterials have been used in drug delivery for many years. They can enhance drug stability, solubility, permeability, and distribution throughout the body. Nanotechnology has the potential to solve many of the challenges PROTAC development faces, but it does add another layer of complexity to drug design and requires expert testing capabilities.
6. Embrace new technologies and breakthroughs
As new technologies and breakthroughs emerge, PROTAC drug developers should embrace new tools and knowledge whenever possible, even if it means casting aside tried and trusted methodologies. Several drug molecules now violate Lipinski’s Rule of Five, suggesting the rule is more flexible than previously thought. New research tools, such as machine learning, can also ensure that innovation continues to accelerate.
Changing PROTACs’ drug delivery systems can help overcome the development challenges. Carriers can enable rapid delivery to disease sites and reduce adverse effects.
Nanomaterials have been used in drug delivery for many years. They can enhance drug stability, solubility, permeability, and distribution throughout the body. Nanotechnology has the potential to solve many of the challenges PROTAC development faces, but it does add another layer of complexity to drug design and requires expert testing capabilities.
6. Embrace new technologies and breakthroughs
As new technologies and breakthroughs emerge, PROTAC drug developers should embrace new tools and knowledge whenever possible, even if it means casting aside tried and trusted methodologies. Several drug molecules now violate Lipinski’s Rule of Five, suggesting the rule is more flexible than previously thought. New research tools, such as machine learning, can also ensure that innovation continues to accelerate.
A final word on developing PROTACs
More PROTAC drugs are in development than ever, and manufacturers are excited about their potential. However, comprehensive testing, data collection, and research are required to fulfill that promise. By collaborating with lab testing partners boasting proven expertise, manufacturers can ensure they face these challenges with an experienced collaborator by their side, ensuring that PROTAC drugs reach the market quickly and safely.
