“If you think of the glue as an open hand receiving Ras, we essentially turn that open hand into a fist that bounces Ras out.”<\/p>\n
Pedro J. Beltran, chief scientific officer, BridgeBio Oncology Therapeutics<\/p>\n
Share Frank McCormick, who studies Ras signaling at the University of California, San Francisco, says the interaction between Ras and PI3K\u03b1 has been known for many years, \u201cbut the significance in cancer has always been rather difficult to figure out.\u201d<\/p>\n Julian Downward<\/a> and colleagues discovered a key insight into this interaction back in 2007 when they genetically engineered mice so that their PI3K\u03b1 could no longer interact with Ras<\/a>. Those mice were resistant to cancers caused by mutant Ras oncogenes (Cell, DOI: 10.1016\/j.cell.2007.03.051).<\/p>\n \u201cThe idea was that if you could actually stop that interaction happening, that might be a good treatment for cancers caused by these mutant Ras cancer genes,\u201d says Downward, who is now associate research director at the Francis Crick Institute.<\/p>\n What\u2019s more, McCormick, who was not involved in that research, points out that the genetically engineered mice were quite healthy. Downward had \u201cestablished using genetics that interrupting that interaction could have therapeutic value and would be safe, at least in mice,\u201d McCormick says.<\/p>\n The problem is that Ras and PI3K\u03b1 interact weakly, which made it tricky to find a drug that could prevent the interaction, McCormick says. But as Downward and McCormick were thinking about preventing this interaction for cancer, scientists at Daiichi Sankyo were trying to enhance the interaction as a way to treat diabetes. They created a molecular glue that stuck Ras and PI3K\u03b1 together<\/a>. In animals, the compound lowered blood glucose levels (Science 2025, DOI: 10.1126\/science.adr9097).<\/p>\n McCormick has a long-standing collaboration with Daiichi Sankyo, and when the scientists there told him about the molecular glue, \u201cI jumped on it and used it to solve the structure of the complex,\u201d he says. McCormick says he wasn\u2019t thinking about creating a breaker at that time. But when he and his colleagues saw that there was a cysteine on PI3K\u03b1 that binds to Ras, it became clear they could use that amino acid as a place to anchor a molecule that could prevent the protein-protein interaction.<\/p>\n That\u2019s when BBOT got involved. The company developed a series of breaker molecules, eventually landing on BBO-10203 as their clinical candidate<\/a> (Science 2025, DOI: 10.1126\/science.adq2004).<\/p>\n \u201cIf you think of the glue as an open hand receiving Ras, we essentially turn that open hand into a fist that bounces Ras out,\u201d BBOT\u2019s Beltran says. BBO-10203 is currently in Phase 1 clinical trials.<\/p>\n BBOT wasn\u2019t the only company thinking about developing a breaker. Vividion\u2019s chief scientific officer Matt Patricelli says that Downward\u2019s genetically engineered mice were truly compelling evidence for what breaking up the Ras-PI3K\u03b1 interaction can do.<\/p>\n This model shows how VVD-442 stabilizes a conformation of PI3K\u03b1 that prevents Ras interaction.<\/p>\n Credit: To try to find a way to disrupt the Ras-PI3K\u03b1 interaction, Vividion scientists looked at covalent fragments in a chemoproteomics screening platform. Those fragments uncovered the same cysteine in PI3K\u03b1\u2019s Ras-binding domain that McCormick\u2019s team had found and showed it was \u201cprimed to react with electrophiles,\u201d Patricelli says. \u201cIt seemed like a fairly easy site to get selective reactions, which is usually what starts us down the path to trying to make a drug.\u201d<\/p>\n Last month, Vividion and Downward reported tool compounds<\/a>, including VVD-442, which are Ras-PI3K\u03b1 breakers (Science 2025, DOI: 10.1126\/science.adv2684). Unlike BBO-10203, which directly blocks the Ras-PI3K\u03b1 interaction, Vividion\u2019s compounds induce a conformational change in PI3K\u03b1 that prevents interaction with Ras. The company also has a breaker compound in Phase 1 clinical trials\u2014VVD-159642\u2014although its structure has not been disclosed.<\/p>\n Patricelli says Vividion saw lackluster results when doing tests with their breakers in cells. \u201cThere was no effect on cell growth in culture, no matter what we did,\u201d he says. But Downward\u2019s animal models were so compelling that the company felt it had to move the compounds into animal models before deciding the program\u2019s fate. That\u2019s when the compounds\u2019 potential became apparent.<\/p>\n Frontier also reported its own Ras-PI3K\u03b1 breaker<\/a>, FMC-242, last month. All three companies say they envision using the breakers in combination with other cancer-fighting drugs, such as Ras inhibitors.<\/p>\n
\n <\/a><\/p>\n
\n Structure of BBO-10203.<\/p>\n
\n A small molecule is positioned between a protein ribbon structure labeled PI3K\u03b1 and a second ribbon structure positioned behind it and labeled Ras.<\/p>\n
\n Vividion Therapeutics<\/p>\n
\n Structure of VVD-442.<\/p>\n
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