Thousands of molecules in the body are known to influence human disease, but it’s challenging to create medicines that can interact effectively with most of them. In fact, it’s estimated that out of roughly 4,000 potential molecular targets, only a quarter actually have a medicine that can get to and act on them.
Sometimes the reasons why a molecular target cannot be affected are highly technical. Other times, the target may simply be too smooth, big or inaccessible.
Researchers sometimes call these difficult targets “undruggable.” But that term isn’t quite accurate because in recent years research advances have brought many of them within reach.
These efforts are already resulting in new therapies, and will likely lead to many more. Below are some strategies Genentech and its collaborators are using to expand the frontiers of the druggable universe.
Macrocycles get between proteins
Many of today’s medicines are small molecules that affect a protein’s function by tucking into a little crevice or niche on its surface. But when two proteins interact with each other in a disease-related process, a small molecule nestled into a crevice on one of them would have little chance of keeping them apart.
This is where macrocycles come in. Macrocycles are ring-shaped molecules that can keep proteins from coming together in unwanted ways. New computational methods allow researchers to perfect these structures for protein-protein interference, giving them the potential to treat diseases that have long evaded traditional small molecules.
RNA modulators fix protein production defects
Typically, after RNA is copied from DNA, but before it can direct protein production, it needs to be modified to remove unnecessary sections. This process is known as RNA splicing. If mistakes occur during the splicing process, the resulting flawed proteins can cause disease.
Through a combination of cell-based screening, bioinformatics and biochemistry, Genentech is developing a better understanding of RNA structure and variations in splicing. With that knowledge, they can develop new small molecule RNA modulators that can eliminate a flawed snippet of RNA from the protein production process. The hope is that RNA modulators can be directed toward challenging targets in cancer and neurological disease.
CIDEs mark molecules for destruction
Cells are efficient. After a protein molecule has served its purpose, it’s tagged for destruction and unceremoniously broken to bits. This natural housekeeping function might be useful as the basis for medicines that are called chemical inducers of degradation (CIDEs), also known as proteolysis targeting chimeras, or PROTACs.
Scientists can design CIDEs to add a molecular tag to a particular protein, marking it for degradation. The advantage of this strategy is its broad applicability because protein degradation is an essential component of nearly every cellular process. It also has longer-lasting effects than a molecular inhibitor, because replacing degraded proteins takes more time than breaking down a small molecule medicine. Virtually any unwanted protein has the potential to be eliminated this way, and Genentech is working on using this approach across a broad spectrum of therapeutic areas.
Delivery technologies pinpoint hard-to-reach targets
For any medicine, it’s crucial that it be able to reach the intended target and modify it without perturbing any similar molecules that are involved in healthy biological processes. One way to improve the precision of a medicine’s effect is by harnessing antibodies.
Antibodies were designed by nature to bind to specific proteins, making them an ideal vehicle for going after one particular molecular target. Antibody-drug conjugates take nature’s design one step further by attaching a medicine to an antibody that binds specifically to the drug’s target, carrying it exactly where it needs to go. Bispecifics represent another modification to natural antibodies, and are able to bind to two targets at the same time as opposed to one. They can help the immune system recognize and destroy cancer by bringing tumor and immune cells together.
These are just a few examples of approaches Genentech is using to drug the “undruggable.” Although not every new idea will lead to a breakthrough medicine, each one expands the understanding of disease at the molecular level and the ability to create new and better medicines. With this systematic approach, Genentech seeks to improve the lives of patients everywhere, one target at a time.
Learn more about how Genentech is working to make the undruggable druggable.