A substantial gap in advancing new treatments for cancer exists because of the lack of effective mechanisms for targeting so-called “undruggable proteins” – proteins known to drive cancer when mutated or overexpressed, but which are not amenable to traditional drug discovery strategies for identifying and optimizing small molecule inhibitors. Recent innovations in targeted protein degradation (TPD), however, have shown exciting potential for overcoming barriers in creating therapeutics against previously undruggable proteins. TPD involves the use of drug-like molecules to selectively cause the destruction of the target protein, rather than simply inhibiting its function. Drugs based on TPD strategies include thalidomide and its analogues, approved for use in myeloma, and PROTAC drugs, originally conceived of by Craig Crews of Yale University and brought to clinical trials in breast and prostate cancer by the company he founded, Arvinas.
The Crews lab is now applying a TPD approach to the develop therapeutics for chordoma, a rare bone cancer of the spine and base of the skull. The main driver of chordoma, known as brachyury (or TBXT), is a transcription factor – one of the most prominent classes of proteins considered undruggable. A past recipient of a Therapeutic Innovation Award presented jointly by the Chordoma Foundation and The Mark Foundation, Dr. Crews will build upon the success of that project to accelerate the optimization and development of what could be the first targeted therapy for this rare and devastating cancer.
Samarasinghe KTG, An E, Genuth MA, Chu L, Holley SA, Crews CM. OligoTRAFTACs: A generalizable method for transcription factor degradation. RSC Chem Biol. 2022.