Author: Jeremy Jerasi, MSc | Contributors: Simon Wu, MSc; Diane Jeon, BCom; Chris Fetterly, PhD

2024 has given me the chance to attend multiple exciting industry conferences involving proteins and their applications in biotech and biopharma. This past October, I represented Future Fields at two conferences: Cambridge Health Institute’s Discovery on Target and Hanson Wades’ Targeted Protein Degradation & Induced Proximity (TPD & IP) Summit. Attending these events in-person gave me a chance to feel the pulse of the TPD field in a way that ChatGPT summaries couldn’t quite capture.

Alessio Ciulli, founder and director of the University of Dundee’s Centre for Targeted Protein Degradation, provided some interesting historical context. The first time these industry leaders in TPD met was at the Discovery on Target conference 10 years ago, where only 20 people attended the small room dedicated to this new field of “protein degradation”. Now, almost 500 attendees attended this TPD Summit representing over 80 companies, focused only on degraders and induced proximity. Notably, this growing industry is about to take off.

From PROTAC’s to DAC’s, there is exciting and explosive progress in this field, as well as great potential to improve human lives by treating diseases previously considered “undruggable.” In this article, I will aim to provide a brief overview of what I learned from key industry and academic leaders, and why I am optimistic about what is coming next in this new field.

Jeremy at the 2024 TPD & IP Conference.

What makes targeted protein degradation and induced proximity different? What does it mean to “degrade” proteins, and why does it matter for patient health? There are many exciting research directions in this field, but I want to focus on where it all started: degradation of proteins via the ubiquitin-proteasome system.

In the body, proteins that are damaged must be destroyed and the amino acids that make them recycled. At the TPD Summit, Christina Woo from Harvard presented her pioneering research exploring the mechanism by which Cereblon (CRBL), a protein known as an “E3 Ligase” is able to cause the degradation of damaged proteins in the cell. Cereblon adds a string of small proteins called “ubiquitin” onto a damaged protein, forming a poly-ubiquitin chain. The proteasome, a large cell structure capable of destroying protein, binds these long poly-ubiquitin chains and leads to the degradation of the damaged protein.

Figure 1: Animation demonstrating the Ubiquitin-Proteasome System (UPS) for protein degradation.

What if, instead of only degrading damaged protein, E3 ligases could be tricked into adding ubiquitin onto a target protein that isn’t damaged, but nonetheless is causing disease? This is exactly what PROTACs (also called bi-functional degraders), and molecular glues are able to accomplish. These drugs are able to “induce the proximity” of the protein target to Cereblon, which is then able to add ubiquitin to the new target and lead to its degradation.

How are these small molecules different from the “classical” small molecule enzyme inhibitors that have been a part of drug development for decades?

Part of answering that question, I learned, lies in the “catalytic” mechanism of these degraders.

Figure 2: Animation demonstrating the differences between small molecule inhibitors (SMI) and bi-functional degraders (PROTACs®).

Fundamentally, small-molecule chemical inhibitors are limited by what Stuart Schreiber at Harvard described in his talk as “Thermodynamic Pharmacology”. Put simply, this means that a single molecule of a drug is only able to affect a single protein at a time. If the chemical is bound to the protein it can exert its effect, but if the chemical falls off, the protein is restored and able to carry out its function (which is causing disease). The consequence of this? You need large amounts of the small molecule to be in the cells, and this means large amounts need to be given regularly to patients. This can cause side-effects and toxicity as the body tries to excrete large amounts of this foreign chemical. Certainly, this limitation has led to many promising drugs failing in the clinic.

PROTAC’s and molecular glue degraders are unique, in that they operate through a catalytic mechanism. When a degrader causes the degradation of a protein, it is not destroyed, and is able to degrade another protein. Fundamentally, a single molecule of these drugs are not limited to only affecting a single protein. This means that with a dose that is 100-1000x lower than classical small molecule drugs, these chemicals can have a powerful effect and degrade close to 100% of the target protein causing disease.

Despite this advantage, one drawback is that these chemicals degrade a target protein in many cells. If the correct protein is degraded, but in a tissue that is not implicated in disease, this is called “on-target, off-site”. If the protein is degraded in tissues that are not disease-relevant, this could lead to side effects and/or toxicity.

CEO panel discussion at TPD & Induced Proximity Summit 2024.

Two approaches to this problem were discussed during the CEO panel at the TPD Summit, where the CEOs of Nurix Therapeutics, C4 Therapeutics, Foghorn Therapeutics, and PhoreMost shared their insights. The first was to focus only on validated biological targets that are primarily expressed in disease-related tissues, to reduce the chance of these problems. The second however, was agreed upon by all the panelists to be an incredibly promising idea: Degrader Antibody Conjugates (DACs).

Figure 3: Animation demonstrating the benefits of conjugating drugs with antibodies.

Antibody-Drug conjugates (or ADC’s) have been an increasingly popular tool, able to deliver specific payloads to specific cell types by using targeting antibodies to direct them to the cells of interest and releasing their payload once inside. However, as previously mentioned, traditional small molecule drugs need to be present at high concentrations in cells due to their “thermodynamic pharmacology”. This is where the degraders could shine, as they do not need to be present at such high amounts due to their catalytic nature. Developing antibodies that bring degrader molecules to specific cell types could avoid the “on-target, off-site” toxicity while still degrading the disease causing protein. Here just a few teams that are working on developing clinical candidates using this technology:

• The first of these DACs just entering the clinic are headed by BMS, who recently purchased Orum Therapeutics GSPT-1 degrader for $100 million up-front.
• In September 2023, Nurix Therapeutics announced a strategic collaboration with Seagen to advance DAC-class cancer therapeutics.
• In February 2024, Firefly Bio launched with $94 million in Series A fundraising based on the promise of this technology. With the 2022 Nobel laureate Carolyn Bertozzi on the leadership team, they are well positioned for many more exciting breakthroughs.

The field of targeted protein degradation offers a new paradigm for drug discovery and is aiming itself at many previous “undruggable” diseases. The new applications of induced proximity including protein degradation and other modalities like protein restoration and modification are incredibly exciting. As the early R&D work continues in academia and industry, researchers are constantly hunting for new ligands for difficult protein targets and ubiquitin ligases.

At Future Fields, we express difficult recombinant proteins and understand that protein quality and cost matters to these researchers. Despite the end goal of modulating protein interactions by inducing proximity, quality recombinant proteins are needed first for early drug discovery and lead optimization. We are eager to play a part in supporting this groundbreaking research by providing high-quality, cost-effective recombinant proteins to enable researchers and accelerate their journey toward transformative therapies.

Questions? Get in touch