Scientists have made a significant breakthrough in targeting a group of molecular switches known as GTPases, which are linked to various diseases including Parkinson’s and cancer. These switches were previously considered ‘undruggable.’
Inspired by drugs developed for the K-Ras oncogene, researchers have found a method to target GTPases, which play a crucial role in multiple diseases due to their malfunctioning.
Researchers at UCSF have learned how to effectively target GTPases, a group of molecular switches implicated in numerous diseases such as Parkinson’s and cancer, which have long been viewed as difficult to treat with drugs.
Due to their complex surfaces, GTPases have mostly eluded modern drug development efforts, with K-Ras being a notable exception. K-Ras is a well-known GTPase that can cause cancer.
The research team decided to test about a dozen drugs designed for K-Ras on several GTPases that they had genetically altered to increase their responsiveness to these drugs. This strategy unveiled new sites where drugs could attach, which were previously undetectable by conventional drug discovery methods.
Published on September 9 in Cell, their findings offer an exciting chance to create treatments for a wide variety of diseases resulting from GTPase dysfunction.
“Although we have known about GTPases for many years, we have struggled to develop effective drugs for them,” mentioned Kevan Shokat, PhD, a UCSF professor in Cellular and Molecular Pharmacology and the study’s senior author. “This discovery really opens up the possibilities for drug discovery targeting GTPases linked to diseases.”
GTPases are essential for cellular functions, controlling processes like molecular movement, cell growth, and division. When these molecular switches fail, it can lead to disease.
In 2013, Shokat and his team identified a specific “pocket” in K-Ras where drugs can bind. K-Ras is a crucial GTPase responsible for around 30% of all cancer cases.
Since then, nearly a dozen drugs targeting K-Ras mutations have been developed, but other GTPases remained untouched.
In their current study, led by postdoctoral researcher and first author Johannes Morstein, PhD, Shokat’s team introduced a common cancer-related mutation, G12C, into a selection of GTPases.
They suspected that G12C, which adds a chemical “hook” to proteins, would help determine which of the ten K-Ras G12C-targeting drugs could potentially bind to other GTPases that share only minor similarities with K-Ras.
The laboratory tests proved successful: G12C enabled some K-Ras drugs to attach to the otherwise unremarkable GTPases, and even after removing G12C, these drugs continued to bind to the GTPases.
This innovative approach, termed chemical genetics, took advantage of the flexibility of GTPases, allowing drugs to force open a pocket in the protein where they could anchor. This pocket was previously missed in computational drug discovery attempts.
“Since GTPases fluctuate between ‘on’ and ‘off’ states, the pocket is not typically accessible, especially not with standard drug discovery software,” Shokat explained. “The drug attaches to an intermediate state, effectively freezing and deactivating the GTPases.”
The researchers are sharing their techniques openly, hoping that others will apply them to target different GTPases of interest, such as those implicated in Alzheimer’s or breast cancer. With hundreds of GTPases available for study, there is significant potential to enhance treatment options for patients.
“For these enzymes, it was essential for us to validate our theories through hands-on laboratory testing to determine what was effective,” Morstein noted. “We believe this can significantly expedite drug discovery.”
