What if we could eliminate selected disease-causing proteins?
It’s an appealing idea, and at BeiGene we BELIEVE we are making it possible with our targeted protein degrader technology:
Chimeric Degradation Activation Compounds
CDACTM
Unlike conventional inhibitor drugs that typically work by binding to and blocking activity of target proteins, CDACs and other degraders work by hijacking a cellular protein recycling process to eliminate target proteins.
Why do we need new approaches to drug discovery?
Proteins may cause or contribute to diseases as a result of their activity, abundance, shape, binding partners, location, or a combination of these and other attributes.
Conventional drugs can be effective at blocking certain activities, but the other properties can be more difficult to address with pharmacologic interventions. By eliminating the target protein, degradation offers a way to address disease targets that have not been amenable to other therapeutic approaches – this is sometimes called ‘drugging the undruggable’. Because of the way degraders work, they may also be effective toward targets that have acquired drug resistance mutations.
How do CDACs work?
CDACs function as molecular matchmakers, recruiting components of the cellular recycling machinery to act on target proteins that they would otherwise ignore. As relatively large ‘small molecules,’ CDACs have two distinct molecular modules linked together.
One end of each CDAC molecule is designed to bind the disease-target protein. The other end binds to a cellular factor called E3 ligase which is part of the protein recycling machinery. When the CDAC pulls these two components together, the E3 ligase system tags the target protein with a small molecule called ubiquitin.
The ubiquitin tag is a label that triggers destruction of the tagged protein by the cellular proteasome system. The interaction brokered by the CDAC may be transient, but as long as the target protein receives a ubiquitin tag, it is destined for destruction. The CDAC can move on to tag the next target, and the next, so a little bit of the CDAC may be able to get rid of a lot of target protein.
What sets BeiGene’s CDACs apart from other degraders?
BeiGene has developed platform chemistry and expertise to generate investigational CDACs that work on a variety of targets. BeiGene’s CDACs are engineered to minimize unwanted immunomodulatory drug (IMiD) activity that is typical of some other degrader drugs that engage a more common E3 ligase. Furthermore, BeiGene is designing CDACs with selectivity for E3 ligases that are absent in tissues commonly associated with toxicity of cancer therapies. This has the potential to preferentially eliminate the target protein in the tumor tissue and not in the normal tissues, where it may be serving a desired function.
What could CDACs mean for patients?
CDACs have the potential to address certain types of drug resistance patients may experience. For example, patients who initially respond to a targeted cancer therapy, but later experience disease progression may be able to benefit from a CDAC therapy that works by eliminating the disease target. In addition, CDACs may make it possible to develop drugs that work on what have been considered undruggable targets, offering new ways to intervene in disease biology, and ultimately improving outcomes and quality of life for patients.
BeiGene’s CDACs
Degraders represent an exciting new approach to drug discovery, with the potential to sidestep resistance mechanisms and drug otherwise undruggable targets.
BeiGene is pioneering degrader technology with its CDAC platform and innovating with impact to bring better medicines forward for cancer patients worldwide.
Visit BeiGene Clinical Trials to see how we’re developing our investigational BTK-targeted CDAC, BGB-16673.