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Apr 26, 2022
By Mohan Iyer
Prothegen: Designing Next Generation Medicines Targeting Ferroptosis

We all need oxygen to survive. But we also need to manage the potential damage that can be caused by oxygen free radicals, which plays a key role in many disorders and diseases. In 2012, Stanford’s Dr. Scott Dixon, spearheaded the discovery of ferroptosis, an iron-mediated form of cell death that is characterized by oxygen free radical-mediated damage to membrane lipids. Davide Zanchi, ex-Roche and current Stanford GSB grad, partnered up with Scott Dixon, as well as chemist Derek Pratt – one of the world’s specialists in free radical chemistry – to form Prothegen. They are leading the way to developing a new class of drugs to regulate ferroptotic cell death with exquisite precision, opening up a new way to approach diseases previously considered untreatable such as stroke, neurodegeneration and cancer.

In a short few months, Davide has assembled a team with deep biology and expert chemistry knowledge necessary to create drugs for lipid oxidation that are way more potent than prior efforts and also able to act where needed most – within the phospholipid bilayer of affected cells. Their first molecule, PTG01, is demonstrated to be safe and efficacious in vitro and in vivo. Equipped with the right mechanism, right location of action, and the right biomarkers, Prothegen is poised to introduce the next generation of medicines targeting ferroptosis.

As I was checking out exhibits on Expo Day, I spotted all 3 founders in one place and got the rare opportunity to pose a few questions to all of them at the same time:

Prof. Derek Pratt being radical about free radical chemistry

What’s really unique about ferroptosis?

Scott:  Ferroptosis is a new type of cell death. What’s unique about it is that it has a different biochemical mechanism compared to known pathways. Because it has a different biochemical mechanism, it presents new targets for drug development. Those new targets turn out to be very important for many diseases, including stroke and neurodegeneration. As you know there is currently a dearth of true disease-modifying therapies for such diseases. So, if we can inhibit those targets, then we can truly turn back the damage from these diseases for the first time.

How do you target ferroptosis?

Derek: Because ferroptosis is driven by oxidation of membrane phospholipids, we actually need to target radicals that propagate the oxidation of membrane phospholipids that are actually then within the lipid bilayer. Many drugs that purported to target lipid peroxidation were targeted to the cytosol and didn’t have activity on lipids in the membrane. Because this is now a chemical reaction, we use small molecules that can intercept the chain carrying radicals, or these propagating radicals to prevent the oxidation of membrane lipids. And that will enable us to save these damaged cells, for the first time.

What does this mean for humans?

Davide: It means that we can pursue indications like ALS, stroke, and other neurodegenerative diseases, wherever ferroptosis is now understood to be a major underlying driver of cell death. We started with CNS indications because 60% of the brain is made of lipids. We now also have the right animal data that predict what our drugs will mean in humans and help us sort through the optimal clinical development path for us. 

There’s only one way to find out more about their confidential animal data: contact Davide today.

What did you accomplish during the IndieBio period?

Davide: When we joined, we had a plan on paper backed by decades of research pointing in the right direction. Within a few busy months after forming the company, we now have a series of first-in-class compounds that can inhibit ferroptosis. Some of these were made internally and some came via our exclusive option to license Derek’s molecules from his university, which we also negotiated during this time. We conducted our first animal models with great results, even without having all the resources and time I would have liked to fully optimize this. IndieBio greatly expanded our networks and we have been actively pitching to investors seeking bold biology approaches to intractable diseases. We are well on our way, having laid down a solid foundation. 

As you leave the program, what are your eyes on?

Davide: The next steps in small molecule drug development are pretty well mapped out – we will optimize the compound, run PK studies, run more animal models, and make sure that the molecule is safe. We are determined to secure a visionary lead investor for our Seed round who truly believes in what we are building. We are being selective with this because we want a solid anchor investor who will stay with us for the long term. We have the biology, the chemistry, the core team, and the right approach to be the world leader in inhibiting ferroptosis.