Twenty years ago, American biochemists Craig Crews and Ray Deshaies developed a revolutionary new technique for attacking pathogenic proteins. As Crews puts it, the concept was to “expand drugs differently. “
Although there are about 20,000 other proteins in the human body, some studies have estimated that less than a quarter of them can be medicated with traditional pharmacological strategies that consist of locating a binding pocket on the surface of the protein to design a small-molecule drug to inhibit it. Its function. .
As a result, the protein targets of many common diseases have remained elusive for a long time, simply because they do not have a suitable binding site or a sufficiently potent inhibitor. In addition, a sufficient amount of the drug is needed in the blood to alter the quality of the drug.
“It’s a brutal approach, binding to proteins and preventing them,” Crews says. “The challenge is that those drugs don’t bind permanently and when they fall off, the unwanted protein becomes unwanted again. So if you want to have two, five, or even ten times more drug to saturate the binding site.
Crews and Deshaies suspected that there would have to be a better method, one that used the plant waste removal mechanism discovered in all cells, known as the ubiquitin-proteasome system. In this system, problematic proteins are sorted for removal by a regulatory protein. called ubiquitin and then degraded through the proteasome.
The researchers designed a two-headed dumbbell-shaped drug called PROTAC with two binding ligands. One can bind to the problem protein and the other can recruit some other enzyme protein called E3 ligase. As a result, a PROTAC brings those two proteins together. allowing the E3 ligase to tag the problematic protein with ubiquitin, marking it for degradation through the proteasome.
“An undoubted merit is that a PROTAC molecule can go through cycles of recruitment, labeling, and destruction, which means it can get away with a lot less of the drug,” Crews says. “I don’t need to promise too much, but in theory, I would recommend that you potentially have fewer side effects. “
Over the past decade, PROTACs have emerged as one of the most exciting new techniques for treating various categories of pathogenic proteins, a technique that is being carried out through biotechnologies and large pharmaceutical corporations. In particular, some corporations are exploring PROTACs as a way to degrade scaffold proteins and prevent them from forming larger protein complexes related to an express disease. Others plan to use them as a new way to modulate the activity of transcription factors, the main regulators that activate various genes in the body’s cells, leading to chronic disease.
One of the leading corporations in this field is Arvinas, which has developed PROTAC in clinical progression for patients with ER/HER2 breast cancer, a domain where desires are meaningful and unsatisfied. Arvinas is expected to publish first-line knowledge from a Phase 3 trial in this patient population later this year. The company is also conducting other ongoing trials in prostate cancer, with PROTAC for B-cell lymphomas and other malignancies in preclinical studies. (Leaps invested in Arvinas in 2019 and the company went public in 2020; Leaps is no longer a shareholder. )
Several other corporations are now pursuing the concept of combining PROTAC with antibody-drug conjugates to allow for more accurate delivery to cancer cells. Poland-based Captor Therapeutics is actively exploring this technique, while in the U. S. it is being explored. In the U. S. , Orum Therapeutics is conducting such a Phase 1 trial. a HER2-expressing breast cancer drug candidate. In November last year, Bristol Myers-Squibb acquired Orum’s drug candidate for the treatment of acute myeloid leukemia and other CD33-expressing malignancies in a deal valued at $180 million.
But while cancer has so far been the main announcement of PROTAC’s development, these targeted approaches to protein degradation may also lead to major advances in the field of neurodegenerative diseases in the coming years, due to the ability of those drugs to cross blood. -Brain barrier.
Arvinas has conducted preclinical studies showing that PROTACs can degrade a scaffold protein called leucine-rich repeat kinase 2 (LRRK2), which has been implicated in the underlying disease process of Parkinson’s disease and a rare neurological disorder called progressive supranuclear palsy. conduct a phase 1 trial of a novel PROTAC for patients with neurodegenerative diseases.
Some of PROTAC’s newer programs may even go beyond chronic diseases and into agriculture. Since the ubiquitin-proteasome formula is conserved in many species, from animals to insects and even plants, PROTACs are now being investigated as new means of pest control. .
In 2019, Leaps and Arvinas jointly founded the agricultural biotechnology company Oerth Bio with the aim of developing PROTACs as new pesticides while reducing the wider environmental impact of agriculture. Earlier this month, Oerth published a new patent demonstrating how PROTACs can degrade. A target protein expressed in insect pests, paving the way for long-term products that can not only protect crops, but also protect favorable organisms. This is a first step forward in a sector desperate for new modalities.
Oerth Bio CEO John Dombrosky describes the need for new crop cover solutions as imperative in the wake of climate change, the growing challenge of pesticide resistance, and increased defense criteria in agriculture.
“Resistance is a critical issue, and new technologies are key to controlling those pest populations,” Dombrosky says. “The impending regulatory review makes this need exponential. By 2035, experts estimate that around $20 billion worth of groundcover products will be withdrawn from the United States. PROTACs provide a promising solution with their inherent defense characteristics and ability to target new mechanisms, avoiding resistance.
In the future, Dombrosky envisions even more transformative uses of PROTACs, to help address some of the difficult situations resulting from the climate upgrade by degrading plant proteins with the goals of helping to mitigate heat stress, water efficiency, and reduce reliance on fertilizers.
Global warming brings with it an increasing risk of vector-borne diseases, such as malaria and dengue, which could begin to spread in Europe and parts of the world where such diseases have never been detected before. A collaboration between BASF Agriculture Solutions, SwissTPH and PROMEGA, funded through the Bill & Melinda Gates Foundation, has begun to look for new tactics to address this emerging fear through PROTAC to alter the critical cellular functions of mosquitoes, affecting their reproductive capacity and thus reducing the rate of disease transmission.
For Crews, the many opportunities presented through PROTACs may be a game-changer in the coming years in the medical and agricultural sectors.
“There are many examples of the use of this protein degradation technique,” he says. “Instead of having to try to genetically modify a plant to make it more resistant to a pathogen or pest, a technique that hasn’t been widely accepted in society, you can now step in and achieve the same result by controlling the proteins that boost the plants’ herbal immune formula or directly the pathogens themselves.
Thanks to David Cox for his additional information on this article.