Designing protein drugs for cancer: New method pinpoints a promising candidate

Scientists design a protein from scratch that specifically blocks cancer target
Dr. Zachary Crook
Dr. Zachary Crook, a postdoctoral research fellow in the Olson Lab, helped design a lab-based method for screening thousands of tiny proteins in human cells. Fred Hutch file photo

When it comes to cancer, there’s no shortage of potential drug targets — many molecules are thrown out of whack when tumors develop. But finding a drug that specifically works against these aberrant molecules is another task entirely. Now, a group led by Fred Hutchinson Cancer Research Center scientists has designed a small protein from scratch that specifically blocks a protein known as TEAD that plays a role in many different cancers.

To find that one engineered protein, the team used a new method developed by Fred Hutch postdoctoral research fellow Dr. Zachary Crook and brain cancer researcher Dr. Jim Olson that is capable of screening thousands of tiny proteins in human cells in the lab. They describe the new technique and the engineered protein in a paper published Thursday in the journal Nature Communications.

The lab-made protein, which is not yet ready for testing in humans or even in animal models, is a tiny knotted protein that can slip in between two cancer-associated proteins: TEAD and its partner in crime, YAP. TEAD normally plays a role in wound healing but is co-opted in a variety of cancers, including those of the breast, liver, colon, lung, prostate, and brain. 

By stopping the two proteins from interacting, the engineered protein could stop them from doing their cancer-promoting jobs.

“Drug companies have been trying to disrupt that interaction for a decade with no real success,” Olson said.

There are very few existing drugs built from this type of tiny protein, also known as a cysteine-dense peptide, or CDP, and fewer still that were designed completely from scratch. Existing protein-based therapies, also known as biologics, are almost universally derived from naturally occurring proteins.

Building protein therapies from scratch is a wide-open field, said Fred Hutch protein design researcher Dr. Phil Bradley, one of the senior authors on the paper. Dr. David Baker of the University of Washington’s Institute for Protein Design (who is also one of the study authors) recently led studies showing that a protein engineered against the flu virus can protect mice from getting sick in laboratory tests. But there are even fewer examples of proteins built from scratch to fight cancer, Bradley said.

“From the perspective of making a completely new protein [cancer therapeutic], depending on how it goes, this could be one of the first,” he said.

Illustration of a designed peptide
Illustration of a designed peptide (blue) sitting on the surface of the TEAD protein (pink). The TEAD protein is involved in a number of different cancers; the engineered peptide could be the starting point for a new protein-based therapeutic. Image courtesy of the Bradley Lab

Crook and Olson believe that CDPs, which fold tightly upon themselves like microscopic knots, could be an untapped goldmine for new cancer drugs. The advantage of these tiny protein tangles is that they may be able to go where no chemical drug can go — including wedging themselves in between two tightly attached proteins like TEAD and YAP.

But it’s really hard to get those little knots to fold correctly in the lab.

Crook and Bradley originally designed their tiny drug-candidate peptide using a computational program that spat out a number of different protein blueprints which, when built and assembled, were predicted to bind to TEAD. To make and test those proteins, they needed a new method.

The technique Crook and Olson developed uses human cells to display thousands of different tiny proteins on their surfaces and a special molecular signaling system that alerts the researchers if one of those tiny proteins attaches to the drug target they’re after, like TEAD. This general method, known as surface display, is not new. Other researchers developed it decades ago, using yeast or bacterial cells, but the existing method hasn’t worked to make and test diverse CDPs, Crook said.

Human cells are much better at making and tying the protein knots, it turns out. So the researchers adapted a human cell line derived from kidney cells to work as a drug-discovery platform. They first tested it on 10,000 of these tiny knot proteins that are found in nature to confirm that the method worked. And then they tested it on the engineered peptides. After a round of tweaks, they ended up with one engineered-from-scratch peptide that deftly interrupts TEAD and YAP from binding to each other, even inside cells.

There’s one big hurdle to face, though: “It can’t penetrate cells by itself,” Crook said. Their next rounds of protein design will aim to fix that problem. Then more laboratory testing and refining.

“We have a lot of work to do, but it already has a far tighter [binding] to its target than anything else we’ve seen out there,” Crook said.

The National Institutes of Health, the Washington Research Foundation and Project Violet funded this study.

Read more about Fred Hutch achievements and accolades.

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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