![What are PROTACs?](https://cdn.prod.website-files.com/644d2ffb3f7ec1eca95b44dd/666b1249cc71c984fd40ad2e_Amyloid_beta_fibrils.png)
Proteolysis is the process in which proteins are broken down into their key components - amino acids and peptides (typically chains of amino acids). Proteolysis targeting chimeras (PROTACs) are a class of drugs that degrade target proteins by hijacking the ubiquitin–proteasome system. This can be desirable to degrade and destroy misfolded or mutated proteins that can lead to certain diseases (cancer, neurodegenerative diseases, etc). Once these proteins are broken down, their amino acids may be used elsewhere in the body or eliminated from the body entirely as waste products.
PROTACs tend to feature properties which can pose a challenge to permeability. The molecular properties and cellular uptake of PROTACs are therefore an important area of study. Most PROTACs fall outside what are traditionally considered drug-like space in terms of their physicochemical properties. Some PROTACs have been shown to be orally bioavailable despite breaking conventional medicinal chemistry rules such as Lipinski’s Rule of Five.
Greater understanding of how PROTACs can be purposefully designed to be orally bioavailable is currently needed, as the discovery of orally bioavailable degraders has thus far been largely serendipitous. Therefore, interest in studying permeability properties of PROTACs is likely to increase in order to more rationally identify candidates for subsequent drug development.