The drug thalidomide has had a long and notorious history. After being shelved in the 1960s for causing birth defects, thalidomide and its analogues were successfully repurposed as multiple myeloma drugs in the late 1990s. However, it wasn’t until 2010 that the target of these compounds was identified to be the hitherto poorly characterized E3 ubiquitin ligase cereblon (CRBN). This discovery catalyzed an explosion in the field of targeted protein degradation, wherein the natural machinery that the cell uses to remove unnecessary proteins is exploited to modulate the levels of targeted proteins of interest. There are currently several clinical trials with novel drugs exploiting this mechanism of action, representing a potential new class of compounds for the modern pharmacopeia.
Despite this scientific gold rush, the endogenous substrate proteins for CRBN have remained unknown for many years. The effort to solve this mystery took a big leap forward in 2022, when Christina Woo’s group showed that CRBN recognizes proteins with C-terminal cyclic imides, a form of protein damage that arises from intramolecular cyclization of glutamine or asparagine residues. These C-terminal imides act as degrons, motifs with are recognized by E3 ligases. This degron is mimicked by the glutarimide moiety found in thalidomide and its analogues, which helps explain the affinity of these compounds for CRBN.
Woo and her group suspect that other forms of protein damage may also be recognized by other E3 ligases in order to remove those proteins from the cell. Proteins are continuously assaulted by chemical damage that results in modifications and loss of function. Common forms include oxidation, dehydration, deamidation, and protein cleavage, which disrupt and eventually kill an organism if left unmitigated. However, the fate and consequences of different forms of protein damage remain relatively unknown. In this ASPIRE award, the group will use a systematic discovery approach to unearth E3 ligases that recognize overlooked modifications occurring in cancer proteomes. They will examine cancer proteomics datasets to predict the existence of modifications arising from protein damage. This will be followed by chemical biology approaches to measure functional recognition of these modifications as degrons. The expected outcome of these studies is to reveal the contribution of protein damage in stabilizing or destabilizing proteins in the context of oncogenesis, and the discovery of novel degrons and their cognate E3 ligase substrate adapters that occur in cancer.