Drugging the Undruggable: The Frontier of Drug Discovery
Conventional wisdom is that approximately 85% of the human proteome was historically deemed undruggable, meaning the proteins cannot be pharmacologically targeted with small molecule drugs.

The traditional pharmacological approach is to inhibit a strategic target protein within a biological pathway affecting disease progression. However, it is often challenging to design a selective and specific small molecule drug for every protein target. A more recent and effective approach has been instead to flag a protein for degradation within the cell. This approach is called targeted protein degradation.

The number of historically undruggable targets available translates into immeasurable opportunities for protein degradation approaches. Consider tumors – large percentages of cancers contain specifically mutated oncogenes. The ability to directly target those mutations could be game-changing for cancer treatments.

Understanding the Targeted Protein Degradation Market
Among new modalities for pursuing undruggable spaces, targeted protein degradation has attracted both attention and substantial pharma industry investment in recent years. One class of new drugs in the protein degradation space is called PROTAC^®, which stands for PROteolysis Targeting Chimera.

These PROTACs are molecules composed of three parts, and each part could be counted as a small molecule itself. There are two different binding domains connected by a linker molecule. The fact that the PROTAC molecule has three different parts suggests that researching it is at least three times more complicated than conventional small molecules.

While PROTACs are by far the most investigated protein degradation modalities, two decades of research in the field has yet to yield an approved drug. Recently launched clinical trials are showing promise, but research needs to accelerate to create sufficient pipeline value for pharma companies to keep pursuing the complex and expensive lab work involved.

Defining PROTAC^®
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules which induce selective proteolysis to remove target proteins by binding them with high selectivity on one end. This side is known as the warhead. The other side binds specifically to a ligase enzyme flagging the target protein, which is now bound to it by the PROTAC for degradation. Between both sides, the PROTAC molecule needs a linker, connecting the two active sides.

PROTACs latch on to proteins which lack the active sites typically required to bind small molecule drugs. This enables ubiquitin-mediated degradation and switches a target from undruggable to druggable. In other words, PROTAC attaches to a target protein and brings this target protein close to special cellular machinery called the proteasome. The proteasome acts like a garbage disposal for proteins and breaks the target protein down into smaller pieces that can be either reused or eliminated by the cell. In theory, this mechanism could be used to treat a disease by eliminating proteins involved in disease pathways.