Scientists unlock new approach to target ‘undruggable’ enzymes
UCSF researchers have developed a novel method to target GTPases, a family of enzymes linked to various diseases including cancer and Parkinson’s, potentially opening new avenues for drug development.
In a significant breakthrough, scientists at the University of California, San Francisco (UCSF) have discovered a way to target a notoriously elusive class of enzymes called GTPases. This development, published in the journal Cell [1] on 9 September 2024, could pave the way for new treatments for a wide range of diseases, from cancer to neurodegenerative disorders.
GTPases: The slippery molecular switches
TGTPases are a family of enzymes that act as molecular switches within cells, controlling various critical processes such as cell growth, division, and movement. When these switches malfunction, it can lead to the development of numerous diseases. Despite their importance in cellular function and disease progression, GTPases have long been considered ‘undruggable’ due to their smooth, featureless surfaces that offer few binding sites for potential drugs.
The breakthrough
Led by Professor Kevan Shokat from UCSF’s Department of Cellular and Molecular Pharmacology, the research team employed an innovative approach to overcome the challenges of targeting GTPases. Their method, dubbed ‘chemical genetics’, builds upon previous successes in targeting K-Ras, a notorious cancer-causing GTPase.
“We’ve known about the GTPases for decades but have lacked any way to reliably drug them,” said Professor Shokat. “This really puts all those GTPases on the map for drug discovery, so it’s possible to target them when they’re associated with disease.”
The team’s approach involved engineering a specific mutation, known as G12C, into a representative group of GTPases. This mutation, which introduces a chemical ‘hook’ onto the protein, allowed the researchers to test existing K-Ras targeting drugs against other GTPases.
Unexpected binding sites revealed
The laboratory experiments yielded surprising results. Some of the K-Ras drugs were able to bind to the typically featureless GTPases with the help of the G12C mutation. Importantly, even after removing the G12C mutation, these drugs continued to bind to the GTPases.
This unexpected outcome revealed new drug binding sites that had eluded previous computational drug discovery efforts. The flexibility of the GTPases allowed the drugs to create and occupy pockets within the protein structure, effectively freezing the enzymes in an inactive state.
“Since these GTPases switch between ‘on’ and ‘off’ states, the pocket is not usually visible, certainly not to the standard software used for drug discovery,” Shokat explained. “Instead, the drug binds to an intermediate state, freezing the GTPases and inactivating them.”
Implications for drug discovery
The findings of this study have significant implications for drug discovery efforts targeting GTPases. By demonstrating that these enzymes can be effectively targeted, the research opens up new possibilities for developing treatments for a wide range of diseases associated with GTPase dysfunction.
Dr Johannes Morstein, the first author of the study and a postdoctoral scholar at UCSF, emphasised the importance of experimental validation in this research. “In the case of these enzymes, it was critical for us to first test our ideas experimentally in the laboratory, to actually see what worked,” Morstein said. “We’re hopeful it can really accelerate drug discovery.”
Potential impact on multiple diseases
The potential applications of this research are vast. Different types of GTPases are implicated in various diseases:
• Rab GTPases are associated with Alzheimer’s disease
• Rac GTPases play a role in breast cancer
• K-Ras is involved in up to 30% of all cancer cases
By providing a method to target these previously ‘undruggable’ enzymes, the research could lead to new therapeutic approaches for these and many other conditions.
Collaborative effort and open science
The study was a collaborative effort, with critical contributions from researchers at Lawrence Livermore National Lab and the National Cancer Institute’s RAS initiative. In the spirit of open science, the UCSF team is sharing their methods openly, encouraging other researchers to apply this approach to their GTPases of interest.
While this research represents a significant step forward, it is important to note that much work remains to be done before these findings can be translated into clinical treatments. The next steps will likely involve further refinement of the approach and extensive testing to identify potential drug candidates for specific GTPases implicated in various diseases.
Reference:
1. Morstein, J., Bowcut, V., Fernando, M., et. al. (September 9, 2024). Scientists learn how to drug wily class of disease-causing enzymes. Cell. https://doi.org/10.1016/j.cell.2024.08.017
