Based on preclinical studies, E1 inhibitors show potential as antitumor agents, but there have been obstacles to getting them into the clinic.
"When you develop a drug, you want it to be highly specific for your protein of interest with no cross-reactivity with other targets or proteins, because that can cause negative side effects," Olsen explains.
It has been difficult to develop E1 inhibitors with specificity for the target of interest. COH000 was initially discovered by Olsen's collaborator at City of Hope, who screened over 300,000 compounds for E1 inhibitors. COH000 was chosen for this study because of its specificity for inhibiting SUMO enzymes, but how the inhibitor works and where it binds to the enzyme were completely unknown.
Thanks to their high-resolution 3D structure and COH000's novel mechanism of action, Olsen and his team may have discovered a new way to overcome this obstacle. Discovery of the new binding site "opens the door" to designing specific inhibitors for other related enzymes as well.
"This inhibitor is different from previous inhibitors," explains Zongyang Lyu, Ph.D., a postdoctoral fellow in Olsen's laboratory and co-first author on the study. "The pocket where the inhibitor binds provides useful information for the refinement of this drug or development of similar inhibitors."
To solve protein structures, Olsen's lab uses a powerful technique called X-ray crystallography. This technique requires a high-energy source that produces intense X-ray beams that hit the crystallized protein and create a distinct diffraction pattern used to determine the 3D structure of the protein.
The most crucial (and often most difficult) part of the process is obtaining a suitable protein crystal.
"Crystals are unique," explains Lyu. "They're an ordered repeat of a single substance with the ability to generate diffraction patterns that allow us to calculate electron density."
The result is a 3D model that allows them to visualize the interaction of potential drug compounds with target proteins (see accompanying video). Eventually, researchers hope this will lead to better treatments for a variety of cancers, including B cell lymphoma, breast cancer, lung cancer and ovarian cancer.
"We're learning the secrets of nature, how these molecules function, and we're doing it in a way that we can actually see with our eyes," Olsen states. "By understanding things at a molecular level, we can use them for the greater good."
Their next step is to use the information from the 3D structure to design more specific and efficient inhibitors with strong antitumor properties.