Researchers Craig Crews and Raymond Deshaies were awarded the 25th annual Jacob and Louis Gabbay Award in Biotechnology and Medicine for the development of the proteolysis-targeting chimera (PROTAC) technology in targeted protein degradation. The Gabbay Award recognizes research that has a distinct practical application that is derived from basic science roots. As described on the award webpage, “…the history of science suggests that most scientific revolutions are sparked by advances in practical areas such as instrumentation and techniques.” PROTACs reveal novel ways to combat drug resistance and expand the number of disease-associated molecular targets.
Many diseases, including cancer, autoimmune disorders and neurodegenerative disorders, have pathologies that are based on the dysfunction of proteins in specific cellular pathways. One strategy that scientists have employed in order to target proteins in cells is by synthesizing small molecule inhibitors that bind to different sites on proteins to reduce their pathogenic activity. Although there is substantial therapeutic interest in developing small molecule inhibitors to malfunctioning proteins, this has proven to be a difficult task to accomplish. Proteins that have multiple domains and complex structure are often difficult to target. Additionally, small molecule inhibitors may have off-target effects with unwanted side effects.
PROTACs offer promising solutions to these problems by increasing target selectivity and enabling greater versatility in the types of proteins that can be targeted. In contrast to traditional pharmacology, PROTACs have the ability to degrade proteins as opposed to just inhibiting them. They were first reported in 2001 by Crews, Deshaies and their team of researchers as a molecule that can target the ubiquitin-dependent proteolysis system. One aspect of the normal cellular maintenance process is the degradation of proteins that are no longer in use. To do this, there are enzymes, or small units of protein machinery, that attach ubiquitin to tag proteins for degradation. The novel therapeutic revelation that the two scientists proposed was to use PROTACs to hijack the cell’s natural ubiquitin-dependent protein degradation system.
PROTACs have two main functions. One part of their structure enables them to bind to a protein of interest and the other part allows the PROTAC to recruit a ubiquitin protein for tagging the protein. The PROTAC then transfers the ubiquitin molecule to the targeted protein. This will alert the cell’s natural proteolysis pathway and break down the protein of interest.
Over the past 20 years since PROTACs were first reported, the development of their therapeutic utilities has moved from academia to industry. The first clinical trials with PROTAC molecules occurred in 2020 and served as the first proof-of-concept that PROTACs could induce the degradation of well-established cancer targets.
Craig Crews is currently the John C. Malone Professor of Molecular, Cellular and Developmental Biology, and holds roles as a Professor of Chemistry, Pharmacology and Management. He is also the executive director of the Yale Center for Molecular Discovery. Raymond Deshaies is currently the Senior Vice President of Global Research at Amgen Inc.. He is also a visiting Professor of Biology at Caltech, where he was formerly a professor.
Moving forward, fundamental research about the function of PROTACs will inform clinical decisions about its therapeutic usage. One active area of research is defining the specific classes of proteins that are best suited for degradation as opposed to inhibition. Another goal is to expand the capabilities of the component of PROTACs that performs the ubiquitination in order to broaden the scope of target diseases beyond oncology.