Unpacking the Cereblon Toolkit, a Q&A with Chris Nasveschuk, Senior Vice President of Chemical Sciences

Chris Nasveschuk, Ph.D., is our senior vice president of chemical sciences. A trained synthetic organic chemist, he’s been with C4T since our early days. In the following “4 Questions with C4T”, he discusses all things Cereblon: what it is, what it does, and its role within our TORPEDO® platform.

DEGGIE: Why is Cereblon so important to our approach to designing degrader medicines?

CHRIS: If there’s a beating heart to our TORPEDO platform, it’s Cereblon. Cereblon is an E3 protein ubiquitin ligase, which is part of a complex called the Cullin 4 ligase complex. Cereblon is 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.

Our 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.

DEGGIE: How does our Cereblon Toolkit contribute to our drug discovery process?

CHRIS: Our Cereblon Toolkit is essential for C4T to create new medicines. Essentially, it’s a collection of small molecule ligands that bind to Cereblon. We deploy the toolkit differently as projects progress from discovery towards the clinic. For example, one of our goals is to optimize catalytic degradation. Here, the toolkit plays a very important role, allowing us to fine tune the binding affinities between ligase and target, and the orientation between ligase and target to see how that influences degradation activity. As we start to understand how the body processes the molecules we’re developing, we can zero in on small molecules that have higher potential for further development.

DEGGIE: How does our Cereblon Toolkit help us design orally bioavailable molecules?

CHRIS: From the toolkit’s early conception we were focused on making sure we built the capability to develop orally bioavailable molecules. We want to give clinicians and patients maximum flexibility with dosing administration and schedule so that the disease can be treated effectively.

Within the Cereblon Toolkit, we have two paths to get to high oral bioavailability. One is controlling specific features of degraders to be within the scope of what is described in the medicinal chemistry field, as beyond rule of five physicochemical property space. The other is to control the effective physicochemical property space by engineering that ability for the heterobifunctional molecule to fold back onto itself.

We have been successful utilizing both strategies to deliver clinical-stage degraders that exhibit high oral bioavailability. We see this in our CFT8634 project targeting BRD9, which is a great example of property control. And, our CFT1946 project targeting BRAF V600X is an excellent example where we engineered the molecule to fold back onto itself.

DEGGIE: How does our Cereblon Toolkit benefit from our MonoDAC™ Library?

CHRIS: The MonoDAC Library is one of my favorite projects. It’s a very chemo-centric approach to expanding the Cereblon Toolkit as we know it. In the early days of C4T, we created about a thousand molecules and tried to map the chemical equity that bound to Cereblon. The MonoDAC Library represents the buildout of that equity to about 10,000 compounds incorporating diverse ideas around our chemical scaffolds that we think are really interesting and have potential for use in both MonoDAC and BiDAC degrader contexts.

Now we’re using the library to go after undruggable targets and try to answer some important questions along the way about each molecule. For example, if we have a molecule that binds to Cereblon tightly, how does it change the surface of Cereblon? How does it change the proteins that engage with Cereblon? This is how the MonoDAC Library enables us to do very bespoke design work that we hope will unlock new targets that we can develop and eventually bring to patients.