Targeted Protein Degraders: Redefining "undruggable"

A look at what targeted protein degraders are, and how they are changing the medical landscape

The proteome of the human body is incredibly vast. Following the hypothesis of one gene codes one protein, the count is approximately 20,000 proteins. However, taking the varied natural RNA- and protein modification mechanisms into account, this number is much higher. When considering phenomena like single amino acid polymorphisms, alternative splicing, RNA editing and post-translational modifications there could be as many as 100 proteins encoded by a single gene. Researchers have proposed that there is up to several billion protein species in the human proteome [1]. The sad truth, and for researchers maddening reality, of this number, is that only an estimated 20–25% of the total proteome is targetable and druggable through conventional small molecule drug technologies. The remaining 80% have, for the longest time, remained undruggable [2].

Newer technologies like gene therapies and siRNA have presented themselves as possibly modalities for tapping into the remaining 80%, but they come with their own hurdles such as delivery issues, efficacy problems and ethical considerations.
Instead, it seems the answer to this issue is to be found in a reinvention of the small molecule drug [2].

Around 1980, a new proteolytic pathway was discovered, involving an ATP-dependant non-lysosomal pathway, using a heat-stable polypeptide which was later identified as ubiquitin. Further research conducted between the 1980s and 1990s showed that this pathway involved three enzymes dubbed E1, E2 and E3 that mediated the binding of ubiquitins to the substrate or protein. Later in this period, a large catalytic protease complex was discovered, known as the 26S protease. A discovery that was awarded the Nobel prize in 2004, with the Nobel laureates being Aaron Ciechanover, Avram Herschko and Irwin Rose [3].

In the early 2000s, scientists were able to exploit this proteolytic pathway, in order to induce the degradation of proteins of interest. In order to do this, scientists used a small molecule drug known as a PROteolysis TArgeting Chimera (PROTAC).

The PROTAC is a bifunctional chimeric small molecule, with two specific binding sites designed to only interact with a protein of interest and an E3 ligase. After binding, the PROTAC is able to recruit E3 enzymes to facilitate the binding of ubiquitin to the protein and mark it for degradation via the proteasome [4].

While revolutionary in and of itself, the PROTAC technology has since expanded with the discovery of molecular glues. These PROTAC-like molecules are able to bind protein surfaces and modify them to induce E3 ligase — protein interactions [5]. Additionally, many more modalities building on PROTACs have been discovered, such as LYTACs and PHOTACs, based on their own unique interactions [6].

In cancers, the tumor-microenvironment contains many mutated protein products facilitating the rapid proliferation of the tumor, allowing it to outcompete and kill healthy cells within the body. As noted, most of these toxic proteins have previously been deemed undruggable, but with the rise of PROTACs these proteins are now obvious targets for inhibiting and possibly even curing cancers [7]. This prospect has not gone unnoticed within the pharmaceutical industry, as the past few years have seen the rapid rise of many companies focusing on the development of PROTACs, molecular glues and many other targeted protein degrading technologies. 
Many big pharma companies like Abbvie (NASDAQ:ABBV), Merck (NASDAQ:MRK) and Bristol-Meyers Squibb (NASDAQ:BMY) are working hard on developing targeted protein degraders, but many other companies have emerged, also betting on this technology. 
Perhaps most notable are the full-blood PROTAC company Arvinas (NASDAQ:ARVN), focusing on battling solid tumor oncologies. Recently Arvinas made a $1 billion deal with Pfizer (NASDAQ:PFE) to develop and commercialize a PROTAC-drug against breast cancer. However, Arvinas is not the only notable player within this space. Others, like C4 Therapeutics (NASDAQ:CCCC) and Kymera (NASDAQ:KYMR) are also focused on leveraging the possibilities laid out by PROTACs against cancers. Alternatively, other smaller, private companies such as Neomorph and BioRap Technologies are also trying to drug the undruggable by utilizing technologies such as molecular glues.

The market for targeted protein degradation is rapidly expanding, and the promise of tapping into the remaining 80% of protein targets is too impactful to ignore. Major deals are being made, as evidenced by companies like Arvinas, and more and more companies are emerging, trying to compete within the landscape of targeted protein degradation. 
At Stargazing Bio Research, we have created a homogenous, quality-controlled database with all the targeted protein degradation companies in the industry. With this database you can get the full picture of the competitive landscape, whether you are an investor looking to gauge the market, a start-up wanting to assess possible competitors, or in an entirely different situation.
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