Immunomodulatory imide drugs (IMIDs) are an important class of medicinal compounds used in the treatment of multiple myeloma. They include the drug thalidomide, as well as its analogues lenalidomide and pomalidomide.
Only in recent years has the mechanism of action for IMIDs in human cells been discovered: the IMID acts as a ‘molecular glue’, bridging together the ubiquitin E3 ligase cereblon with a variety of other proteins, known as ‘neosubstrates’. After binding to cereblon, the neosubstrates become polyubiquinated and subsequently degraded - the cellular ‘kiss of death’.
Many of cereblon’s neosubstrates share a common region based on a zinc finger motif. Structural studies have shown that this motif - known as a ‘degron’ - is required for the neosubstrate to bind to the cereblon/IMID binary complex. Furthermore, this degron can be added to genes for other, unrelated proteins, resulting in a fusion protein that contains an inducible off-switch. Addition of an IMID will cause the fusion protein to become polyubiquitinated and degraded.
Thalidomide and its known analogues are not always suitable for this kind of system, as they have a variety of off-target effects. My research aims to explore how the structures of both the IMID small molecule inducer and the fusion protein’s degron can be modified so that the IMID/degron ‘off switch’ system is orthogonal: i.e. the small molecule will only interact with its intended target, and not any of the natural, degron-containing proteins present in human cells.