PROTACs in agriculture could combat pests, mitigate heat stress, improve water efficiency and reduce ... [+]
Two decades ago, the American biochemists Craig Crews and Ray Deshaies hit on a revolutionary new approach for targeting disease-causing proteins. As Crews puts it, the underlying idea was “to do drug development differently.”
While there are approximately 20,000 different proteins in the human body, some studies have estimated that less than a quarter of them are druggable using conventional pharmacological methods of finding a binding pocket on the protein surface for designing a small molecule drug, and thus inhibiting its function.
As a result, protein targets for many common diseases have long remained elusive, purely because they lack a suitable binding site or a strong enough inhibitor. In addition, the need to maintain sufficient drug levels in the bloodstream to disrupt the function of the right protein can give rise to side effects.
“It’s a bit of a sledgehammer approach, binding to proteins and stopping them,” says Crews. “The problem is that these drugs don’t bind permanently, and when they fall off, the rogue protein becomes rogue again. So you need to have two times, five times, maybe even 10 times as much drug around to saturate the binding site.”
Crews and Deshaies suspected that there must be a better way, one which utilized the natural garbage disposal machinery present within all cells, known as the ubiquitin-proteasome system. In this system, problematic proteins are tagged for removal by a regulatory protein called ubiquitin and then degraded by the proteasome.
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The researchers devised a two-headed dumbbell-shaped drug called a PROTAC with two binding ligands. One site can attach to the problematic protein and the other can recruit another enzymatic protein called an E3 ligase. As a result, a PROTAC brings those two proteins together, which results in the E3 ligase tagging the problematic protein with ubiquitin, marking it out for degradation by the proteasome.
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“A distinct advantage is that one PROTAC molecule can do multiple rounds of recruiting, tagging and destruction, which means that you can get away with a lot less drug,” says Crews. “I don't want to promise too much, but in theory, that would suggest that you could have potentially fewer side effects.”
Over the last ten years, PROTACs have emerged as one of the most exciting new approaches for drugging multiple classes of disease-causing proteins, one which is being pursued by both biotechs and large pharma. In particular, some companies are exploring PROTACs as a way of degrading scaffolding proteins and preventing them forming larger protein complexes associated with a specific disease. Others are looking at utilising them as a novel way of modulating the activity of transcription factors, the master regulators which turn on various genes in cells around the body, sometimes leading to chronic illness.
One of the leading companies in this space is Arvinas which has developed the only PROTAC in clinical development for patients with ER+/HER2- breast cancer, an area of high unmet need. Arvinas is expected to report topline data for a Phase 3 trial in this patient population later this year. The company also has further ongoing trials in prostate cancer, with PROTACs aimed at 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 companies are now pursuing the idea of combining PROTACs with antibody-drug conjugates as a way of enabling more precise delivery to cancer cells. Poland-based Captor Therapeutics is actively exploring this approach while in the U.S., Orum Therapeutics is conducting a Phase 1 trial of such a drug candidate for HER2-expressing breast cancer. In November of last year, Bristol Myers-Squibb acquired Orum’s drug candidate for the treatment of acute myeloid leukaemia and other CD33-expressing malignancies in a deal worth $180 million.
But while cancer has been the main commercial focus of PROTAC development so far, such targeted protein degradation approaches could also yield major breakthroughs in neurodegenerative diseases in the coming years, due to the ability of these drugs to cross the blood-brain barrier.
Arvinas has conducted preclinical studies showing that PROTACs can degrade a scaffolding protein called leucine-rich repeat kinase 2 (LRRK2) which has been implicated in the underlying disease process of both Parkinson’s disease and a rare neurological condition called progressive supranuclear palsy. The company is now conducting a Phase 1 trial of a novel PROTAC aimed at patients with neurodegenerative diseases.
Some of the newer applications of PROTACs could even stretch far beyond chronic illness and into the realm of agriculture. Because the ubiquitin-proteasome system is conserved in many species from animals to insects and even plants, PROTACs are now being studied as a novel means of pest control.
In 2019, Leaps and Arvinas jointly created the agricultural biotech company Oerth Bio with the aim of developing PROTACs as novel pesticides, while simultaneously reducing the wider environmental impact of agriculture. Earlier this month, Oerth published a new patent demonstrating how PROTACs can degrade a specific target protein in insect pests, setting the stage for future products that can not only safeguard crops but also protect beneficial organisms. This is a major breakthrough in a field that is in desperate search for new modalities.
Oerth Bio’s CEO John Dombrosky describes the need for novel crop protection solutions as imperative in the wake of shifting climates, the growing problem of pesticide resistance, and heightened safety standards in agriculture.
“Resistances are a critical issue, and new technologies are essential to control these pesky pest populations,” says Dombrosky. “Impending regulatory scrutiny makes this need exponential. By 2035, experts estimate that around $20 billion of crop protection products will be taken off the market. PROTACs present a promising solution with their inherent safety features and capacity to target novel mechanisms, thus circumventing resistance.”
In the future, Dombrosky envisions even more transformative uses of PROTACs, to help address some of the challenges resulting from climate change through degrading protein targets in plants to help mitigate heat stress, improve water efficiency, and reduce fertilizer dependence.
With the warming world comes an increasing threat of vector-borne diseases such as malaria and dengue, which may begin to spread to Europe and parts of the globe where such diseases have never previously been seen. A collaboration between BASF Agricultural Solutions, SwissTPH and PROMEGA, funded by the Bill and Melinda Gates Foundation, has begun to research new ways of tackling this emerging concern through using PROTACs to disrupt critical cellular functions in mosquitos, affecting their reproductive ability and thus lowering disease transmission rates.
For Crews, the many possibilities offered by PROTACs could prove game-changing in the years to come across both the medical and agriculture sectors.
“There are many instances of how this protein degradation approach can be used,” he says. “Rather than having to try and genetically modify a plant to make it more resistant to a pathogen or pest, an approach which has not been widely accepted by society, you can now come in and achieve the same result by controlling proteins that either boost the natural plant immune system or directly affect those pathogens themselves.”
Thank you to David Cox for additional research and reporting on this article.
