The PROTAC Technology in Drug Development

PROTAC (Proteolysis Targeting Chimeras) is a concept of protein degradation targeting consortia, which was first proposed by Yale University professor Craig Crews and others in 2001. It uses the body's naturally occurring protein-cleaning system to treat disease by reducing protein levels rather than inhibiting protein function. After 20 years of development, PROTAC technology has become one of the most popular technologies in the field of new drug research and development.

Fig. 1. An exemplar PROTAC showing the three basic units of target-binding ligand, linker and E3 ligase ligand (Journal of Medicinal Chemistry. 2018, 61(2): 444).

PROTAC Therapeutics

Compared with traditional small molecule drugs, PROTAC-based protein degraders have unique advantages. One of the biggest advantages is the ability to target difficult-to-drug targets or mutant proteins. Research shows that currently less than 20% of the targets in drug development are targeted, and up to 80% of protein targets cannot be intervened through traditional drug development methods. In addition, PROTAC molecules do not need to bind to the target protein for a long time before they can degrade the target protein and completely eliminate its function, which is expected to solve the drug resistance problem that often occurs with small molecule inhibitors.

Fig. 2. Schematic of PROTAC action (Journal of Medicinal Chemistry. 2018, 61(2): 444).

The original PROTAC technology used peptides as ligands and successfully targeted targets such as MetAP-2, androgen receptor (AR), estrogen receptor alpha (Erα), and phosphatidylinositol 3-kinase (PI3K). This lays a good theoretical foundation for the development of small molecule PROTACs. Subsequently, small molecule ligands for E3 ubiquitin ligases such as CRL4CRBN, CRL2VHL, and cIAP were discovered, providing a new direction for the development of PROTAC technology. Currently, PROTAC is mainly used in the field of cancer, mainly targeting nuclear receptors, epigenetic proteins, kinases, other types of proteins/enzymes, and RNA.

PROTAC Technology Advantages

Potential for Treating Undruggable Targets

The mode of action of traditional small molecule drugs is "occupancy drive". That is, the drug needs to bind to the target protein at high intensity for a long time, and occupy the active site of the target at high concentration to block the downstream signaling pathway. Thereby inhibiting the function of the target protein and achieving the effect of treating the disease. The mode of action of PROTAC is "event-driven". It can work as long as a ligand can bind, so it can act on some targets that small molecules cannot bind to.

Overcoming Drug Resistance Issues

Because PROTAC technology by degrading the entire protein molecule rather than just its activation site, it can bypass the mutation or variation on the target, against drug resistance.

Catalysis

PROTAC brings the target protein closer to the E3 ubiquitin ligase and performs ubiquitination, ultimately leading to the degradation of the target protein. PROTAC can break away from target proteins and E3 ligases and achieve intracellular recycling. Each PROTAC molecule can degrade many protein molecules, so a lower dose can achieve better drug efficacy.

PROTAC in Clinical Trial

After more than two decades of development, PROTAC technology has been successfully transferred from academia to industry. In 2019, the first PROTAC drug entered clinical trials. In 2020, PROTAC targeting estrogen receptor (ER) and androgen receptor (AR) cancer targets completed clinical proof-of-concept, and subsequently, a variety of drugs advanced to the clinical stage. As of June 2023, 28 PROTAC drugs have entered the clinical development stage worldwide (Table 1), including 1 clinical phase III, 7 clinical phase II, and 20 clinical phase I. In addition, there are 376 drugs in the preclinical development stage. At present, PROTAC drug research and development covers more mature drug targets such as ER, AR, and BTK, and its indications are mainly prostate cancer, breast cancer, and hematological tumors.

Table 1. Example of PROTAC for clinical research.

PROTAC Linkers

PEG linkers are commonly used in the field of PROTACs. PEG linkers play a crucial role in PROTAC design as they act as flexible spacers between ligands that bind target proteins and ligands that recruit protein degradation machinery. These linkers allow for optimal positioning of the two ligands, promoting the formation of a ternary complex between the target protein, the PROTAC molecule, and the E3 ubiquitin ligase. The use of PEG linkers in PROTAC offers several advantages. First off, PEG linkers can increase the solubility, stability, and pharmacokinetics of PROTAC molecules. The flexibility of the linker improves the stability and bioavailability of PROTAC, and the hydrophilicity of PEG helps increase water solubility. In addition, PEG linkers offer the flexibility and space between ligands required for effective binding of target proteins and E3 ubiquitin ligases. The PEG linker's flexibility and length can be adjusted to enhance the binding affinity and selectivity of PROTACs. Also, by improving the selectivity of PROTACs, PEG linkers can aid in reducing off-target effects. By adding a PEG linker, the binding ligand is placed such that interactions with undesired proteins are minimized, decreasing the possibility of unforeseen side effects.

PEG & PROTAC Solutions

To satisfy unique client needs, BOC Sciences provides a broad variety of PEG products with various molecular weights and functional groups. These PEG solutions can be used into various formulations as solvents, dispersants, lubricants, and stabilizers. Given that PEGylation enhances the stability, solubility, and pharmacokinetics of medicines, they can also be employed as drug delivery methods. Moreover, BOC Sciences provides a wide array of PROTAC solutions for the development and discovery of new drugs. Because of their excellent potency, selectivity, and stability, our PROTAC solutions are useful instruments for researching protein function and creating fresh therapies.

Reference

1. Churcher, I. Protac-induced Protein Degradation in Drug Discovery: Breaking the Rules - or Just Making New Ones? Journal of Medicinal Chemistry. 2018, 61(2): 444.