Proteasomes to the Rescue


Many drugs work by stopping overactive proteins that cause disease. The leukemia drug Gleevec, for example, is a small-molecule inhibitor (antagonist) of the protein Bcr-Abl, whose over-activity promotes excessive cell division. Humira treats a range of autoimmune diseases by stopping TNF-alpha, a protein that activates inflammation.

Such antagonists can be powerful. However, it’s not always possible to develop a strong inhibitor of a disease-associated protein. And when scientists do develop them, resistance often emerges, rendering a drug ineffective.

What if, instead of merely inhibiting a protein, we could totally get rid of it? It turns out that our cells already have that ability. In this Biotech Primer WEEKLY, we look at a new class of drugs scientists are developing to take advantage of our bodies’ microscopic sanitation departments.

A Cellular Garbage Disposal


If allowed to accumulate, proteins can interfere with normal cell function. Therefore, all cells contain proteasomes, compartments that break apart unneeded or damaged proteins. Proteasomal degradation also provides a way to recycle the amino acid building blocks of proteins. Once a protein is broken down, a cell can use the leftover amino acid “bits” to rebuild new proteins.

Proteins are targeted for degradation through the action of E3 ligase. This enzyme attaches another protein, ubiquitin, to the targeted protein. Ubiquitin then guides the target into a proteasome, where it’s broken down. If scientists figure out how to “tag” disease-associated proteins with ubiquitin, they can activate our cellular garbage disposal to fight illness. Several companies are working on clever ways to do just that.

Small Molecules, Big Results?


Researchers at Arvinas (New Haven, CT) are developing a platform to target disease-causing proteins based on ubiquitination/proteasome systems. Dubbed PROTAC (Proteolysis-Targeting Chimera), the platform consists of “bifunctional small molecules” – which simultaneously bind to two different proteins.

With PROTAC, one end binds to the target, the other to E3 ligase. This interaction transfers ubiquitin to the target protein for eventual disposal. PROTAC doesn’t necessarily have to recognize a specific part of the target, such as the active site of an enzyme. That allows researchers to focus on a wider range of proteins than possible with existing technologies, such as small molecule inhibitors, which must fit precisely in an enzyme’s active site to work.

Arvinas has released preclinical data suggesting that PROTAC successfully lowers levels of the protein BRD4 in lymphoma, multiple myeloma, and prostate cancer cells.  BRD4 plays a role in cell division, and mutated versions are associated with various cancers. In the past year, Arvinas announced collaborations with Pfizer and Genentech, which should speed the progress of getting these molecules to the clinic.

C4 Therapeutics (Cambridge, MA) is developing a similar small molecule platform that connects disease-associated proteins with cellular ubiquitination enzymes. Dubbed “degronimids,” the molecules are still in preclinical development. They have already attracted the attention of Google-backed Calico, with whom C4 recently signed a five-year deal to work together to treat diseases of aging.

Kymera (Cambridge, MA) is also utilizing small molecules to activate target-specific proteasome degradation, focusing first on oncology and autoimmunity. In March, Celgene (Summit, NJ) announced a project with Vividion (La Jolla, CA) in the hopes of discovering ubiquitin-proteasome system interacting drugs.

Now Wait a Second…


It’s clear that many drug developers place great faith in tapping proteasome power to advance human health. In what could seem completely contradictory, other companies are taking the opposite approach: squelching the proteasome.

The process of apoptosis, or programmed cell death, occurs naturally in cells as a protective mechanism. For example, cells that sustain large amounts of damage to DNA activate apoptosis to prevent them from seeding a tumor.

Many pharmaceutical companies are trying to co-opt apoptosis to treat cancer. One way to induce the process is to inhibit the action of proteasomes. The resulting buildup of damaged proteins signals the cell that something is seriously amiss, setting off cell death.

The FDA has approved Velcade, marketed by Millennium Pharmaceuticals(Cambridge, MA), to treat multiple myeloma. Krypolis, developed by Onyx (South San Francisco), is another proteasome inhibitor approved as a second-line treatment for multiple myeloma. Both are small molecule drugs.

A better understanding of how our cells process unwanted proteins has opened up an entirely new approach to treating diseases. Manipulating the world’s tiniest garbage disposals may hold the key to healing otherwise untreatable conditions.


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