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Drug Discovery

Inhibitor takes down many forms of KRas

Blocking these cancer-linked proteins stops tumor growth in mice

by Bethany Halford
June 7, 2023


Structure of BI-2865.

A small molecule that blocks mutants of the protein KRas could guide drugmakers to new treatments for cancers associated with these proteins. In tests with cells, the molecule, known as BI-2865, acted as an inhibitor of many KRas mutants as well as wild-type KRas, which is amplified in some cancers. It didn’t block HRas or NRas proteins, which are structurally similar to KRas and perform important functions in regulating cell growth, differentiation, and survival (Nature 2023, DOI: 10.1038/s41586-023-06123-3).

“You go back 20 years, and everyone said KRas was completely undruggable,” says Darryl B. McConnell, a medicinal chemist at Boehringer Ingelheim who worked on the discovery of BI-2865. Chemists simply couldn’t find a place for an inhibitor to bind to the smooth surface of KRas and its mutants. But one of the mutants—KRas G12C, in which a glycine in the wild-type protein is replaced by a cysteine—proved vulnerable to inhibitors that could covalently latch onto the cysteine residue when the protein was in its inactive state. This finding led to several drugs to treat cancers that have the KRas G12C mutation, including Amgen’s sotorasib and Mirati’s adagrasib. The fact that BI-2865 can noncovalently block many KRas mutants shows that most of them are druggable, McConnell says.

The research team, which was led by Piro Lito at Memorial Sloan Kettering Cancer Center, also developed a modified version of BI-2865 that could be given to animals. This molecule, known as BI-2493, stopped tumor growth in mice. McConnell says that BI-2865 and BI-2493 are tool compounds, not clinical candidates. But their effectiveness shows that the strategy for inhibiting multiple KRas mutants works.

BI-2865 and BI-2493 also block wild-type KRas, which could be beneficial for treating cancers where the protein is amplified or could have a detrimental effect on cellular processes. “I think the whole field is very anxious to see how these agents perform in the clinic and understand how much wild-type KRas inhibition can be tolerated in this class of drugs,” Kevan Shokat, a scientist at the University of California, San Francisco, who studies KRas, says in an email.

“Therapeutics that address all of the KRas mutations that drive human cancers are urgently needed, and this work represents a significant advance toward this goal,” Victor Cee, who worked on the discovery of sotorasib, says in an email. Cee is currently senior vice president of drug discovery at Hexagon Bio. That Lito’s team was able to find inhibitors for many KRas mutants that do not also inhibit HRas or NRas is “a remarkable achievement,” Cee says. “It is not hard to imagine that we will see a number of pan-mutant KRas inhibitors entering clinical testing over the next few years.”



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