PROTACs Enter the Clinic: A Brief History

Protein degradation has been an evolving technology for decades. The principle is simple: to co-opt the cell’s own in-built machinery for destroying target proteins by marking them as unwanted, prompting their degradation. It offers significant advantages in a number of therapeutic areas over other modalities. Chief among these advantages is the potential to open up a vast space of currently undruggable proteins, such as those which have no active sites and cannot be targeted by more conventional means – such as small molecule inhibitors. 

PROTACs: How they work

When referring to targeted protein degradation, the primary modality to achieve this is proteolysis targeting chimeras – PROTACs, although similar technologies that achieve degradation also exist. PROTACs are heterobispecific – binding to two different proteins inside the cell. One end of the PROTAC binds to the target protein, while the other end recruits a ubiquitin ligase and brings it in proximity to the target protein which is then ubiquitinated, marking the target for subsequent degradation by proteasomes. The PROTAC is not used up in the process, which means that it can perform this function repeatedly – enabling lower dosage of possible drug candidates and more durable responses.

The first compound of this kind to be published in a study, Protac-1. which targeted methionine aminopeptidase-2 (MetAP-2) – a cancer-related protein. The effects of Protac-1 were clear, showing the compound was capable of driving MetAP-2 degradation. The study also identified what would be the major challenge of delivering these results in humans: PROTACs were simply too big and unlikely to penetrate cellular membranes without further modification or assistance. This limitation kept the technology on the fringes of pharma for a long time, even though PROTACs showed great functionality and promise.

Structural and Chemical Considerations

PROTACs were thus understood to be “pharmacokinetically risky” molecules that violated the most commonly accepted rules for what makes a drug safe: low molecular weight, low lipophilicity, low surface polarity – and others. Various modifications can be made to improve either their passive permeability, or facilitate active transport across cell membranes. Among them is the development of PROTACs with lower molecular weight, or compounds which can assume different conformations depending on the environment they find themselves in. Newer research also shows the potential to replace amide bonds with ester bonds to improve permeability. Future innovations in the field are only expected to improve the pharmacokinetic and pharmacodynamic profile of the modality – particularly their distribution in the body and their internalization by targeted cells.

Like many conjugated drugs, PROTACs rely on linkers to connect the two main parts of the compound together. Studies have determined that the nature of the linker can play a crucial role in its function: too short, and function may be impaired. Different lengths have also demonstrated changes in target selectivity, possibly related to the conformation the PROTAC and its targets assume, and their subsequent steric interactions, when binding occurs. One of the most promising advancements in improving our understanding of the protein-protein interactions of PROTACs and the complexes they form is PRosettaC. This is a tool, based on the Rosetta protein structure prediction suite of algorithms and computational models, which has the potential to truly jumpstart the development of future PROTAC drug candidates. 

PROTACs enter the Clinic

Over the last decade, PROTACs made their transition to the industry – with multiple large pharmaceutical companies and startups showing interest and pouring resources into improving the viability of the technology. This has resulted in multiple product candidates moving from preclinical development into the clinic, making PROTACs the first drug modality of multispecific chimeras to do so. There are currently 15 different candidates in clinical trials – the majority of which target solid or liquid tumors, with one also investigating the treatment of autoimmune diseases. Three of those products are still at the IND stage, while only two have made it to Phase II trials so far.

Both Phase II products were developed by Arvinas, a company dedicated to the advancement of PROTACs. Their first, and earlier, product, ARV-110, targets prostate cancer. Phase I investigations of ARV-110 in castration-resistant metastatic prostate cancer showed an acceptable safety profile, as well as potential tumor reductions. Combined with interim Phase 2 results, ARV-110 has so far demonstrated a >50% reduction in Prostate-Specific Antigen (PSA, one of the chief markers of prostate cancer) in over 46% patients. This shows the potential for PROTACs to provide solutions in areas where all other current treatment modalities have failed.

ARV-471 is the only other PROTAC in Phase II trials, developed to combat breast cancer by Arvinas in partnership with Pfizer. ARV-471 targets estrogen receptors, and is currently being investigated in patients with locally advanced and metastatic breast cancer. ARV-471 has so far shown great reductions in estrogen receptors in treatment groups – up to 89%, with partial responses also observed in at least two patients. Additionally, ARV-471 is also being investigated in combination therapy palbociclib – which is currently in Phase 1b trials.

With PROTACs making their journey across the clinic, their other uses are also becoming apparent. These include uses beyond the pharmaceutical field altogether – with possible applications in agriculture and the wider food industry. The protein degradation offered by PROTACs can enable fine-tuned manipulation of the proteome of crops, and other industrial microorganisms such as yeast, at a level similar to gene editing or transcription interference, showing the extremely wide horizons for the modality in the future. 

After years of investigation, PROTACs have shown that their inherent advantages over other modalities – their oral bioavailability, low dosage, persistent effects and potential to provide solutions to unmet needs – make them worth investigating despite their inherent challenges. These challenges are slowly being overcome through chemical and structural innovations in our drug discovery process – and PROTACs have already entered the clinic. The future remains bright for chimeric modalities – with other modes of treatment such as RIBOTACs expected to follow soon in the future.

Nick Zoukas, Former Editor, PharmaFEATURES

Join Proventa International’s Medicinal Chemistry Strategy Meeting in London to hear more on the latest developments in targeted protein degradation, as well as join leading experts on discussing the cutting-edge subjects of the field in a closed door roundtable format. Exchange ideas and forge new collaborations in an environment catering to both academia and industry.