Antagonists Fight A Good Fight

Small molecule inhibitors, also known as antagonists in the industry, fight a good fight. In fact, many drugs on the market today work by inhibiting overactive, disease-associated proteins. Novartis’ (Basel, Switzerland) top selling leukemia drug Gleevec, for example, is a small molecule inhibitor of a protein called Bcr-Abl, whose overactivity promotes excessive cell division.

The downside? It is hard to develop effective small molecule inhibitors.  The best inhibitors are designed by knowing the shape of the target—information which is often difficult to get. Even if researchers do know the shape of the target, it may not be one for which an effective inhibitor can be designed. This is because the part of the protein that is overactive, for example, may be a smooth or flat surface and inhibitors need something to “hook onto”. And for those proteins for which scientists are able to develop strong inhibitors, resistance may emerge, rendering the drug ineffective.

What if, instead of inhibiting disease-associated proteins, we could simply dump ’em? It turns out, cells already have a system for getting rid of defective proteins. So, let’s unwrap a new class of drugs taking advantage of these tiny cellular garbage disposals and find out how we might just drug the undruggable.

Like A Garbage Disposal

All cells contain specialized compartments called proteasomes whose job is to degrade unneeded or damaged proteins. Like a garbage disposal, proteasomes are hollow on the inside in order to enclose and break down the peptide bonds that hold the proteins together.

Proteins are targeted for degradation via the action of an enzyme called E3 ligase. E3 ligase first instructs the protein ubiquitin to attach to the unneeded protein. Then, ubiquitin guides the protein into the proteasome chamber, where it is broken down for disposal. This process enables the cell to regulate protein concentration and dump any misfolded proteins.

Meddling In The Middle

Arvinas (New Haven, CT) is developing a platform to target disease-causing proteins based on the ubiquitin and proteasome interaction. Dubbed PROTAC (Proteolysis-Targeting Chimera), the technology consists of “bifunctional small molecules”—small molecules that have been designed to simultaneously bind to two different things.

In the case of PROTAC, one end binds to the target disease-causing protein and the other end to the E3 ligase. This interaction triggers the transfer of an ubiquitin protein to the target, marking it for degradation. The whole complex is then degraded and dumped by the proteasome. Since the PROTAC doesn’t necessarily have to recognize a very specific part of the target protein, it is possible to target a wider range of proteins compared to existing technologies.

Arvinas has released preclinical results on their platform’s ability to target the protein BRD4, which plays a role in cell division. Mutated versions of BRD4 are associated with various cancers. Data suggests PROTAC has successfully lowered levels of the protein in lymphoma, multiple myeloma, and prostate cancer cells.

Term Of The Week: Druggability

Druggability refers to whether or not it is possible to develop a drug that will bind to a particular target, and alter the function of that target in a disease-modifying way. The structure of the target is a key determinant of druggability. It’s been estimated that only about 2% of human proteins interact with currently approved drugs, and only about 10% to 15% of human proteins are druggable using today’s technology—and these druggable proteins may or may not actually be disease-associated (source). These numbers underscore the importance of developing new technologies for drug discovery.

The disease-associated proteins inhibited by antagonists on the market are druggable proteins. But, because antagonists are hard to make, and resistance may develop over time, the need for additional avenues is clear. Platforms such as PROTAC—and even RNA-based technology—circumvent the need to inhibit a protein by halting the production of the protein in the first place.

RNA To The Rescue?

RNA-based drugs are another approach to putting a dent in the undruggable proteins of today. Recall from high school biology that RNA translates DNA code into a language ribosomes can understand in order to make proteins required by the cell. Messenger RNA (mRNA) is the intermediary between genes and proteins: a gene is transcribed into mRNA, and that mRNA is translated into chains of amino acids—the building blocks of proteins. Because these drugs target the mRNA transcript of a protein rather than the protein itself, they do not require a protein structure that is accessible to drugs. Read more about RNA-based platforms like RNAi, antisense and more in our previous issue.

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