After 2 decades of stalled attempts to target the human oncogene RAS, a drug discovery team from Genentech has finally made headway. Using a novel screening method, the team discovered a pocket on the RAS oncoprotein's surface in which small molecules can bind and, in turn, interrupt activation.
“We think of this as a breakthrough advancement that would provide new directions for drug development for the RAS oncoprotein,” says senior scientist Guowei Fang, PhD, who presented these findings at the American Society for Cell Biology's annual meeting in Denver in December. RAS mutations are found in 25% of human cancers and are a clinical marker for poor prognosis.
Traditional screening methods that look for small molecules to stop RAS activity have come up short. “We screened more than 1.4 million compounds using activity-based screening and didn't get any matches,” says Fang.
![A small-molecule ligand (red) binds to a site on the Ras protein (yellow) and blocks Ras activation by SOS1 (blue-gray). In early structural analyses of other GTPases—a class of more than 150 proteins found in all human cells and involved in a wide range of cellular processes—a Genentech team found that some have the same binding pocket, suggesting GTPases may be a very viable class of drug targets. [Photo courtesy of Genentech]](https://aacr.silverchair-cdn.com/aacr/content_public/journal/cancerdiscovery/2/1/10.1158_2159-8290.cd-nb120811ol-15/6/m_5photo1.jpeg?Expires=1683091736&Signature=hKa5SLkBGHQb2YzcsbKyTiFORlFp49UTQ82DQyW999dePYfmw138bExvi5kxanMBgDmXPayFyz6R7FHRKjOsgrn6xS-dDKhikk4C93Zc7asOh4bXBnMbdWPr6qj3N30JLHc9e7g~UoYuqKf1j6gA1MZMEHCFpokn~lOxefBaKzH5Rwi1ZPFQVa3kqvlFluNmV14prYjxcom3H3DxGSAd1xM2PP~6~JdfIH7Tn6BooDIZdLZ95~w6~pRLafL9vMzYiwDbDRpDlstp7w9d3avu7RB16I1sfx3ntkmsO1BRW7F7pvb0BwtkEJDS9rKH-RL3nsLUnoEik1yKdwlbet-flw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
A small-molecule ligand (red) binds to a site on the Ras protein (yellow) and blocks Ras activation by SOS1 (blue-gray). In early structural analyses of other GTPases—a class of more than 150 proteins found in all human cells and involved in a wide range of cellular processes—a Genentech team found that some have the same binding pocket, suggesting GTPases may be a very viable class of drug targets. [Photo courtesy of Genentech]
A small-molecule ligand (red) binds to a site on the Ras protein (yellow) and blocks Ras activation by SOS1 (blue-gray). In early structural analyses of other GTPases—a class of more than 150 proteins found in all human cells and involved in a wide range of cellular processes—a Genentech team found that some have the same binding pocket, suggesting GTPases may be a very viable class of drug targets. [Photo courtesy of Genentech]
In this new work, Fang and his colleagues instead used fragment-based lead discovery. They screened highly soluble fragments of small molecules at high concentrations and used nuclear magnetic resonance spectroscopy to identify fragments that bind with RAS. “We use this approach to probe the RAS protein structure for a binding pocket,” said Fang. “RAS has a smooth surface topology, so it's hard to find a pocket.”
Of 3,300 screened fragment compounds, 25 bound to RAS. These 25 fragment compounds all bound in the same pocket, a site very close to the place where RAS binds with SOS, a co-factor that switches RAS from off to on. “Our compounds interrupt the RAS–SOS interaction and block the nucleotide exchange reaction that activates RAS,” says Fang. Further, when Fang and colleagues applied these compounds to a cellular model, RAS activity dropped by 50%.
The team confirmed that their compounds bind with K-Ras and H-Ras, 2 of the 3 Ras isoforms. “The 3 isoforms are very similar in structure, so I don't expect selectivity,” says Fang.
The binding affinity of these first-generation compounds, however, is too low, so they are not viable drug candidates. “This work is a starting point for further drug development,” says Fang, who also found that the binding pocket can be enlarged. “This gives us an opening for mixing more compounds and improving affinity.”
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