Each day our cells clean up faulty and unneeded proteins. In this process, called protein degradation, cells look for cues to know which proteins are undesirable. Think of it like “please remove” tags stuck to misshapen proteins. Now, scientists are learning how to place these tags on disease-relevant proteins — like brachyury, the key driver of chordoma. If brachyury could be tagged for removal, chordoma could be defeated via the body’s natural clean-up process.
In this exciting project, Dr. Craig Crews at Yale University is using a powerful, emerging technology called PROteolysis TArgeting Chimeras (PROTACs) to leverage the body’s innate protein degradation process against brachyury. A pioneer in this field, Dr. Crews has two decades of experience in protein degradation research and was one of the inventors of PROTACs technology. PROTACs are two-sided molecules that bind on one end to disease-relevant proteins, and on the other end to the cellular machinery that tags them for degradation.
Brachyury belongs to a class of proteins called transcription factors, which were historically considered “undruggable” because they lack a known active site to which a traditional drug could form a strong bond and disrupt function. A key advantage of PROTACs is that they require neither a specific active site to interfere with nor a strong bond. PROTACs thus could make it possible to eliminate disease-causing proteins like brachyury that were previously inaccessible to medicine.
In the first phase of this research, Dr. Crews’ lab used computer modeling to identify sites on brachyury where PROTACs could land. The team will also screen libraries of existing small molecules to identify compounds that show promise in their ability to interact with brachyury. Building on these brachyury binders, they will design and optimize PROTACS capable of triggering its degradation.
Progress in brachyury-targeting PROTACs could yield new treatments that are likely to have an impact far beyond chordoma, because brachyury plays a role in metastasis in many other cancers. Plus, this project makes brachyury one of the first transcription factors against which PROTACs are being developed — meaning its success could help pave the way for development of treatments against additional transcription factors, which play a role in many other diseases, including at least a quarter of all cancers.
Content Courtesy of The Chordoma Foundation.
Samarasinghe KTG, Jaime-Figueroa S, Burgess M, Nalawansha DA, Dai K, Hu Z, Bebenek A, Holley SA, Crews CM. Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell Chem Biol. 2021.