Unpacking the Cereblon Toolkit: Advancing the Science of Degrader Discovery

If there’s a beating heart to C4T’s TORPEDO platform, it’s Cereblon. Cereblon is an E3 protein ubiquitin ligase, and the only ligase universally distributed across all tissues and cellular compartments in the body. Cereblon is also one of the many initiators in the body’s natural degradation process. It tags proteins of interest with ubiquitin and in rapid succession, which builds a ubiquitin chain in a process called polyubiquitination. This sets up a signaling cascade that directs targeted proteins to the proteasome for degradation. We harness this natural process to target and eliminate disease-causing proteins. To date, Cereblon is the only clinically validated E3 ligase for targeted protein degradation.

C4T’s drug hunters focus on Cereblon, using it as one of the focal points that our chemical matter engages in the protein degradation process. We’ve designed a number of different chemical scaffolds that bind to Cereblon. We combine those scaffolds with molecules that recruit the targeted proteins we want to degrade. Then we conduct a series of tests to measure how tightly they bind to Cereblon, the target protein, and in the cellular context, how rapidly these molecules degrade the protein of interest. This part of our discovery process can be summed up as a kinetic assessment: the change in disease-causing protein level in the cell per unit time.

From there, we use our TORPEDO platform to measure the pharmacokinetic profiles of these molecules—how the body processes and clears the molecule—and perform in vivo testing to understand their pharmacodynamics—how they affect the target and the disease. This whole process, which hinges on Cereblon, drives important decisions about which molecules we decide to move toward the clinic.