Fragment Covalent Bond Formation at SOS1 Tyr-884 Inhibits KRAS Nucleotide Exchange

Fragment 11 (SOF-599) forms a covalent adduct predominantly at SOS1 Tyr-884 and inhibits KRAS nucleotide exchange with a KI of 12 micromolar.

• Why it matters: SOS1 activates KRAS by promoting GDP-to-GTP exchange, and current small-molecule inhibitors disrupt SOS1–KRAS interactions but may not fully exploit covalent targeting.
• What they did: The study screened aryl sulfonyl fluoride fragment libraries, used X-ray crystallography plus mass spectrometry and nucleotide exchange assays with wild-type and mutant SOS1, then selected Tyr-884–specific fragment 11 (SOF-599).
• The result: Fragment 11 (SOF-599) inhibited SOS1-driven KRAS nucleotide exchange in a time- and concentration-dependent manner, with a reaction half-life of 6 h, supporting covalent SOS1 inhibitor development.

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