Chemical Inducers of Degradation (CIDEs)

CIDEs tag disease-causing proteins for destruction.

CIDEs tag disease-causing proteins for destruction by binding both the target protein and a ubiquitin ligase. The ubiquitin ligase transfers ubiquitin to the target, flagging it for destruction by a protein-degrading complex known as a proteasome. In addition to improving the therapeutic properties of CIDEs, we are exploring ways to combine these molecules with other treatment strategies.

Cells are efficient. After a protein molecule has served its purpose, it’s tagged for destruction and unceremoniously broken to bits. In cases where a disease-related protein is difficult to access by other means, this natural housekeeping function might be useful as the basis for medicines that we call chemical inducers of degradation, or CIDEs. These are also known as proteolysis targeting chimeras, or PROTACs.

Normally, cells designate unwanted proteins for disposal with a molecular tag called ubiquitin, which alerts the body’s natural degradation system. A CIDE is a double-ended molecule that scientists can manipulate to add ubiquitin to proteins, thereby marking the target of interest for degradation. The advantage of this strategy is its broad applicability, because protein degradation is an essential component of nearly every cellular process.

Degrading a disease-causing protein with the cell’s own machinery, rather than inhibiting it with a small molecule or biologic, offers a number of advantages. “What makes CIDEs attractive is that they’re possibly more potent than small molecule inhibitors. The effect of an inhibitor disappears once the drug is cleared from the body, but if you degrade a target protein, it has to be remade before it becomes active again, providing a sustained therapeutic effect,” says Ingrid Wertz, Senior Scientist, Discovery Oncology & Early Discovery Biochemistry and Genentech Degrader Team Lead.

Moreover, unlike inhibitors, CIDEs may be useful even if they don’t interfere with the target’s function. Research suggests they only need to attach to a protein well enough to enable the degradation process.

Because CIDEs have so many potential advantages, we’re working to improve their therapeutic properties and collaborating with others to advance clinical applications of protein degradation.

One area of development involves attaching CIDEs to antibodies, known as antibody-mediated delivery, to home in on a particular protein target. “We can use the specificity of antibodies to direct CIDE compounds to the tissue of interest, and thereby minimize their effects elsewhere,” says Robert Blake, Senior Scientist, Biochemical and Cellular Pharmacology.

We’re also investigating ways to expand the realm of targets that we can go after. We may be able to achieve this through covalent targeting. Due to the nature of their molecular interactions, covalent bonds may provide improved potency and selectivity, and widen the range of targets that CIDEs can act on. “What we’re hoping to do is find applications that wouldn’t be achievable through non-covalent approaches,” explains Wertz.

The first clinical applications of CIDEs will be in oncology, particularly for slowing tumor growth. Yet with potential utility in virtually all types of cells, it is hoped that CIDEs may find application in therapeutic areas from neurodegeneration to infectious disease and immunology as well.