Despite well-established tumorigenic roles of KRAS mutants, targeting their smooth surfaces was a challenge, which was overcome through the development of G12C-specific covalent inhibitors. A new study shows that optimizing non-covalent interactions with a cryptic pocket produces remarkable potency for another hotspot mutation.
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Marshall, C.B., Ikura, M. Hitting the hotspots. Nat Chem Biol 18, 578–579 (2022). https://doi.org/10.1038/s41589-022-01000-y
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DOI: https://doi.org/10.1038/s41589-022-01000-y
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Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS
Signal Transduction and Targeted Therapy (2023)