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Significance The development of K-Ras G12C covalent inhibitors suggests that this strategy could lead to therapeutic agents directly targeting Ras. Unfortunately, the overwhelming majority of Ras mutants and all Ral proteins do not have an accessible cysteine residue. Screening of a covalent fragment library containing aryl sulfonyl fluorides led to the discovery of one compound class that formed a covalent bond with noncatalytic residue Tyr-82. Remarkably, a high-resolution crystal structure at 1.2-Å resolution revealed that the compound created a deep hydrophobic pocket that was never previously observed in Ras or Ral GTPases. This binding pocket has a SiteMap DrugScore that is identical to druggable kinase ATP-binding pockets, suggesting that it could be used to develop therapeutics targeting oncogenic Ras lacking cysteine.

Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases