Researchers from the University of Dundee and Promega Corporation have developed a method to improve the efficacy of targeted protein degradation, an area of chemical biology employed in drug discovery. The research on this "three-headed hydra" approach has been published in Nature Chemical Biology.
Targeted protein degradation involves co-opting a cell’s natural disposal systems to remove disease causing proteins. This system is applicable to therapeutic areas including oncology, inflammation, dermatology, immunology, and respiratory diseases.
Degrading a target protein reportedly offers several advantages over traditional inhibitors. This type of drug may show a greater response at lower doses, and is more precise with potentially reduced side effects and disease resistance. The first compounds in this class, termed Proteolysis-targeting chimeras (PROTACs), are being trialled as candidate medicines against various cancers and progressing through clinical trials.
PROTACs are conventionally small molecules designed with two heads, called bivalent or heterobifunctional compounds. However, research carried out by Dundee’s Centre for Targeted Protein Degradation (CeTPD) in collaboration with biotechnology company Promega has now indicated degraders can be significantly improved by making them trivalent, i.e., consisting of three heads.
The best trivalent PROTAC designed by the researchers proved to be remarkably more potent than their bivalent predecessor compounds, Promega claims, showing stronger anti-cancer activity at a much lower dose and improved pharmacological responses across a wider dose range.
“Three heads can be better than two in PROTACs,” said Dr Alessio Ciulli, Director of the Center for Targeted Protein Degradation. “We hypothesised that we could improve degraders by latching onto the target protein more productively. To do this, we designed trivalent PROTACs by adding an additional protein-binding ligand, in effect creating a three-headed monster that destroys cancer-causing proteins more effectively.”
The researchers concluded the trivalent PROTAC concept could improve on many aspects of degrader drug action and, in future, be applied to a wider range of protein targets.
