Drugging GTPases beyond KRas

Although there are more than 150 guanosine triphosphate (GTP)–binding proteins, or GTPases, only the GTPase KRas G12C is susceptible to small-molecule drugs. That’s because it’s tough to find a spot for small molecules to bind to GTPases. Now, researchers have used what they know about the weak spot in KRas G12C to locate a toehold for small molecules on other GTPases. The finding could lead to new drugs and biological probes. GTPases are involved in many cellular processes. They bind GTP and hydrolyze it to guanosine diphosphate. In doing so, they function as molecular switches in many biological processes. GTPases have been implicated in cancer and neurodegeneration. “You could find them in almost any disease area,” says Kevan M. Shokat , a chemical biologist at the University of California, San Francisco, who led the research. GTPases were considered undruggable until 2013. That’s when scientists in Shokat’s lab showed that the