In healthy cells, the protein MYC helps guide the process of transcription, in which genetic information is converted from DNA into RNA and, eventually, into proteins. However, the shapeless protein is responsible for making the majority of human cancer cases worse. Finding a way to control MYC is challenging because unlike most other proteins, MYC has no structure. Now, researchers from the University of California (UC), Riverside, report they have discovered a way to tame MYC, offering a potential pathway to new treatments.
Their findings are published in the Journal of the American Chemical Society in an article titled, “MYC-Targeting Inhibitors Generated from a Stereodiversified Bicyclic Peptide Library.”
“Here, we present the second generation of our bicyclic peptide library (NTB), featuring a stereodiversified structure and a simplified construction strategy,” the researchers wrote. We utilized a tandem ring-opening metathesis and ring-closing metathesis reaction (ROM-RCM) to cyclize the linear peptide library in a single step, representing the first reported instance of this reaction being applied to the preparation of macrocyclic peptides.”
“MYC is less like food for cancer cells and more like a steroid that promotes cancer’s rapid growth,” Min Xue, PhD, associate professor of chemistry, said. “That is why MYC is a culprit in 75% of all human cancer cases.”
In 2018, the researchers noticed that changing the rigidity and shape of a peptide improves its ability to interact with structureless protein targets such as MYC.
“Peptides can assume a variety of forms, shapes, and positions,” Xue said. “Once you bend and connect them to form rings, they cannot adopt other possible forms, so they then have a low level of randomness. This helps with the binding.”
In the study, the researchers describe a new peptide that binds directly to MYC with what is called sub-micro-molar affinity, which is getting closer to the strength of an antibody.
“We improved the binding performance of this peptide over previous versions by two orders of magnitude,” Xue said. “This makes it closer to our drug development goals.”
Currently, the researchers are using lipid nanoparticles to deliver the peptide into cells. These are small spheres made of fatty molecules, and they are not ideal for use as a drug. Going forward, the researchers are developing chemistry that improves the lead peptide’s ability to get inside cells.
Once the peptide is in the cell, it will bind to MYC, changing MYC’s physical properties and preventing it from performing transcription activities.
“MYC represents chaos, basically, because it lacks structure. That, and its direct impact on so many types of cancer make it one of the holy grails of cancer drug development,” Xue said. “We are very excited that it is now within our grasp.”