Creating Orally Bioavailable Degrader Medicines to Push the Boundaries of Scientific Discovery – with Kate Jackson, Senior Director of Chemistry

At C4T, we’re constantly striving to push the boundaries of scientific discovery. This centers around targeted protein degradation as a new modality, and we take it a step further by focusing our research on orally bioavailable degraders. We believe degraders have the potential to truly transform how medicine is practiced—for patients, caregivers and healthcare providers.

Designing oral degraders is not easy. Due to their complex structure, degraders fall outside the traditional small molecule property space and don’t easily satisfy Lipinski’s Rule of Five, a set of guidelines on chemical properties that help predict whether a chemical compound will be orally bioavailable.

Kate Jackson, Ph.D., our senior director of chemistry explains further: “The challenge of protein degraders specifically is that we’re not dealing with traditional small, easy to manipulate molecules. Many of them are large, floppy structures. We would not normally expect molecules of this size and shape to be well absorbed in the gut when swallowed as a pill.”

Despite these challenges, thanks to a team focused on pushing the boundaries of scientific discovery, C4T has developed orally bioavailable degrader molecules that break Lipinski’s Rule of Five. “Our degraders defy many of the rules that have been established to achieve oral bioavailability,” Kate continued. “To achieve this feat, sometimes we have to play tricks with the molecules. Imagine you have a camping tent to break down. The poles are very long. However, when each pole is collapsed, it takes up less space. In some cases, we’ve found ways to fold our molecules in on themselves such that they appear smaller and can more easily traverse through membranes in our cells and in our gut.”

With two orally bioavailable degraders in clinical trials, we are now learning how our molecules may benefit patients. At the same time, our drug developers continue to challenge themselves to design molecules that further advance targeted protein degradation research. As Kate explains, “The discovery of new and orally bioavailable degrader medicines will necessitate continued creativity and innovation, and the scientists at C4T are up to the task.”