Molecule Takes On Deadly Cancer By Inhibiting ‘Unfolded Protein Response’

By Deborah Borfitz 

June 22, 2023 | Researchers in a joint European network report on a specially developed molecule known as Z4P that could deliver fresh hope to patients with glioblastoma, the most aggressive malignant primary brain tumor with a less than 7% survival rate five years post-diagnosis. As an adjunct to gold-standard chemotherapy, Z4P effectively inhibits the stress management pathway of cancer cells so they self-destruct, according to Leif Eriksson, professor of physical chemistry at the University of Gothenburg (Sweden). 

In a newly published study in iScience (DOI: 10.1016/j.isci.2023.106687), he and his team demonstrated that Z4P passes the blood-brain barrier and stops cancer growth in mice when administered together with chemotherapy. Rodents given the combination therapy notably had no cancer relapse after 200 days, twice as long as the animals treated with just chemotherapy, and they experienced no side effects in terms of weight loss, changes in behavior, and liver damage.  

Specifically, Z4P restrains inositol-requiring enzyme 1 (IRE1), a major mediator of the “unfolded protein response” that fast-growing glioblastoma cells adaptively use to cope with a pace of protein production that surpasses its ability to properly fold them, explains Eriksson. The folding of proteins is done largely by an organelle known as the endoplasmic reticulum. 

When the system senses it is overloaded, the stress is overcome by relying on IRE1 signaling to switch the endoplasmic reticulum from making proteins to degrading them to alleviate the burden, Eriksson says. Blocking the process in healthy cells is not an issue since they don’t suffer that much stress to begin with, he adds, referencing extensive cell testing where Z4P was shown to be non-toxic even when administered at very high doses. 

Since Z4P can get into the brain, this opens the possibility of treating glioblastoma patients without the need for surgery and radiation treatments to reach the tumor, he continues. Other aggressive tumor forms where the unfolded protein response is heavily upregulated—a list that includes pancreatic cancer and triple-negative breast cancer—might similarly benefit from the substance. 

The other cancer types in the brain don’t have that same signature, says Eriksson. Still, glioblastoma accounts for about 45% of all brain tumors and strikes 250,000 people worldwide annually.   

Last Molecule Standing

Collaborators on the project are researchers affiliated with the National Institute for Health and Medical Research (INSERM) in Rennes, France, in particular the group led by Research Director Eric Chevet, Ph.D. focused on understanding the unfolded protein response, says Eriksson, a computational chemist. Development of Z4P involved using supercomputers to screen large databases and running long simulations to assess the ability of ligands to bind to the active site of the IRE1 protein. 

Chevet’s group had previously shown that small segments of IRE1 itself could block the protein’s mode of action, so researchers decided to use a database of tetra- and penta-peptides to see if any of them would bind to the targeted active site, he says. With that information they created the “pharmacophore,” or three-dimensional plot of the interaction landscape, to use as a filter to identify compounds that precisely fit that map. 

The pharmacophore screen found structurally new IRE1 modulator candidates, and the two best ones were chosen to be further characterized and tested for their ability to modulate IRE1 activity in vitro, says Eriksson. One was excluded from further analysis due to its high toxicity profile, eventually leaving Z4P as the last molecule standing for more extensive testing that included demonstrating that it permeates the blood-brain barrier. 

Work on the promising molecule continues, including tweaking its chemical properties to make it slightly more stable, he reports. While experiments on mice continue, studies will ultimately extend to larger animals such as dogs or pigs to better predict the appropriate dose and expected treatment duration for preventing cancer recurrence in humans. 

To enable next steps on the “long journey” toward the clinic, the research team is now seeking venture capital to secure needed funding, says Eriksson. Whether that leads to the creation of a university spinoff or partnership with a big pharma company remains to be seen.