Protein Degraders Take Industry By Storm

What is protein degradation?

According to Nello Mainolfi, CEO of Kymera Therapeutics (NASDAQ: KYMR), practically every big pharma player and medium-sized biotech business today has internal R&D research or external collaborations in the field of protein degraders. The boom sparked by these small molecule therapies is due to a number of causes, which we will cover in this article, together with notable companies in the field, and three case studies revealing innovative strategies to go about designing targeted protein degraders.

Small molecule inhibitors (SMIs), one of the most commonly used methods of treating illnesses, have essential limitations. SMIs can currently reach protein targets of only around 20% of the proteome. According to the medical journal EBioMedicine, over 75% of known proteins lack active sites for SMIs binding, which means that traditional therapeutics can't inhibit their function. To overcome the limitations, researchers took a fresh approach to small molecules, turning an old tool into a novel therapy.

The idea began to take shape in the 1990s, when Proteonix, a biotech company, submitted a patent for a bifunctional molecule that targets the ubiquitin-proteasome system (UPS). Even though Proteonix never developed a medication based on the patent, it kicked off two decades of active research in the field. The first Proteolysis targeting chimera (PROTAC) was introduced in 2001, and it consisted of two ligands connected by a flexible linker. The basic chemical architecture of modern PROTACs is the same: one ligand targets the E3 enzyme, which is a component that sends outdated proteins to the proteasome, and another ligand targets a protein of interest (POI) that has to be degraded. A PROTAC binds E3 and POI, bringing them closer to form an induced proximity complex. In some cases, when the proteins align appropriately, the POI gets ubiquitinated, which marks it for degradation by the proteasome.

Another broad approach to protein degradation includes so-called “molecular glues,” an actively growing area of research. In contrast to PROTACs, being relatively large bifunctional small molecules with two active sites and a linker, molecular glues are smaller and more drug-like molecules. The latter bind to an aggregate protein pocket resulting from two separate proteins coming into proximity due to the effect of the molecular glue molecule. While this article primarily focuses on the bifunctional protein degraders, there is an excellent overview of molecular glues in the 2022 C&EN article “Molecular glues are beginning to stick. “

Advantageous therapeutic modality

PROTACs and other targeted protein degraders have an advantage over conventional small molecule inhibitors because of their unique mechanism of action. To maximize the therapeutic potential of SMIs, high and frequent doses are usually needed because one needs a stoichiometric ratio of the SMI and POI (i.e., occupancy-based pharmacology). However, one PROTAC molecule can trigger the breakdown of several POI molecules through the catalytic mechanism. Thus PROTACs require substantially lower concentrations in the cell to achieve efficacy. This phenomenon has the potential benefit of lowering a drug's toxicity and improving its side effect profile. As such, the factor that defines the efficacy of a PROTAC is not the affinity but the kinetics of binding — a measure of how rapidly a PROTAC can bring both targets together to start the process. As a result, chimeras can function by binding to every nook or cranny of a protein, possibly extending the pool of druggable target options.

The race for better degraders