Degrader takes out many forms of KRas

The enzyme KRas has become a popular cancer target for drugmakers in the last decade, with many companies developing small molecules that inhibit one or multiple KRas mutants. Now, scientists are reporting a compound that eliminates multiple KRas mutants using an alternative strategy—targeted protein degradation. The compound could lead to new therapeutics and help scientists compare inhibition versus degradation when tackling KRas.

Researchers led by the University of Dundee’s Alessio Ciulli and Boehringer Ingelheim’s Peter Ettmayer developed the degrader, which they named ACBI3. One-half of the molecule features a moiety based on an inhibitor reported last year that targets multiple forms of KRas. This group is linked to a moiety that binds to the von Hippel–Lindau (VHL) E3 ubiquitin ligase, which tags proteins for destruction by the proteasome—often called the cell’s garbage-disposal system (Science 2024, DOI: 10.1126/science.adm8684).

Using a crystal structure of an early bifunctional compound bound to a KRas mutant and VHL was key to developing ACBI3, Ciulli and Ettmayer say. “It allowed us to illuminate the binding mode, which is almost like a hook,” Ciulli says, where one part of the degrader is buried deeply within KRas, and the other part binds tightly within VHL, priming KRas for degradation.

Degrading a protein can have a different pharmacological effect than simply inhibiting it, Ciulli and Ettmayer say. A treatment that degrades a protein instead of simply blocking it can potentially last longer and be effective at lower doses. In their paper, the researchers compared degradation versus inhibition of KRas. “We did find greater impact downstream in the pharmacology” for the degrader, Ciulli says.

Although degraders that target specific KRas mutants have been reported, this degrader is able to take out 13 of the 17 most common KRas mutants in test tube studies. That includes KRas G12D, which is the mutant that’s most prevalent in cancer. ACBI3 was also able to shrink KRas mutant tumors in mice when the compound was injected into their abdominal cavities.

Justin Taylor, who studies degraders at the University of Miami Miller School of Medicine and was not involved in the work, says the results are promising. He points out that the KRas-targeting drugs currently on the market are effective only against the mutant KRas G12C. “A pan-KRas targeting agent would allow a broader number of cancer patients to receive potential benefits from treatment with these agents,” he says in an email.

But Taylor says that while the researchers figured out how to administer their compound in mice, they still need to show they can dose it in people. “Therefore, this serves as a proof of concept rather than a therapy that is going to be readily available soon,” he says.