UCSF researchers have made a groundbreaking discovery on how to drug GTPases, enzymes previously deemed ‘undruggable,’ potentially revolutionizing treatment for a wide range of diseases including cancer and Parkinson’s.
UCSF scientists have succeeded in drugging a class of molecular switches called GTPases, linked to numerous diseases ranging from Parkinson’s disease to various cancers. This breakthrough could potentially lead to the development of new treatments for these conditions, previously thought to be untreatable.
GTPases, crucial regulators in cellular function, become problematic when they malfunction, leading to diseases. Traditionally, their elusive nature has rendered them “undruggable.” But for the first time, UCSF researchers have found a method that could unlock a plethora of new therapies.
“We’ve known about the GTPases for decades but have lacked any way to reliably drug them,” senior author Kevan Shokat, a UCSF professor in the Department of Cellular and Molecular Pharmacology, said in a news release. “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 researchers drew inspiration from previous work on K-Ras, a notorious cancer-causing GTPase, which gave rise to targeted drugs. In an ingenious leap, the team hypothesized that similar tactics could be used on other GTPases. They employed a dozen drugs known to target K-Ras against various mutated GTPases, unexpectedly uncovering new drug binding sites.
In 2013, Shokat’s team made a pioneering discovery finding a binding pocket on K-Ras. That revelation turned into a turning point allowing the development of approximately a dozen drugs to treat K-Ras mutations. However, success with K-Ras didn’t extend to other GTPases until now.
Leading this innovative research was UCSF postdoctoral scholar Johannes Morstein, who alongside his team engineered a commonly mutated form of K-Ras, G12C, into other GTPases. The G12C mutation, which introduces a chemical hook onto the protein, assisted the researchers in identifying other druggable GTPases.
“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 added. “Instead, the drug binds to an intermediate state, freezing the GTPases and inactivating them.”
This experimental approach, dubbed chemical genetics, revealed a previously hidden flexibility in the GTPases, allowing the drugs to secure a snug fit within their structure. The technique expands possibilities for treating various diseases associated with different GTPases.
“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 in the news release. “We’re hopeful it can really accelerate drug discovery.”
The implications of this discovery are far-reaching. Given that GTPases play a role in conditions like Alzheimer’s and breast cancer, this research opens the door to potential new treatments across a spectrum of diseases.
The study, published in the journal Cell, also included significant contributions from Lawrence Livermore National Laboratory and the National Cancer Institute’s RAS initiative, as well as other UCSF researchers. The collaborative study reflects a concerted effort toward untapping the potential of GTPase-targeting therapies.
With this research, the world of drug discovery turns a new leaf. By sharing their methods openly, UCSF researchers aim to spur further innovations, allowing scientists globally to explore these methods in targeting disease-related GTPases. This progressive move could mean new hope for millions suffering from diseases once believed to be untouchable.