Covalent fragments reach lysines in the SHP2 allosteric latch site
- Combines an electrophile-first covalent fragment screen with a ligand-first strategy to target lysines in the allosteric latch site of SHP2 phosphatase.
- Computational and experimental analyses support the binding mode, and the work yields what the authors call the first potent, cell-active allosteric covalent inhibitors at this site.
- It shows the latch site is covalently tractable, opening routes to new allosteric SHP2 chemotypes.
💡 Points
Lysine-directed covalent chemistry is far rarer than cysteine, so a workflow that actually delivers cell-active hits on a lysine is the takeaway, more than SHP2 itself. My caveat is reactivity versus stability: lysine electrophiles can be hydrolytically fragile or reversible, so I'd want proteome-wide selectivity data before calling anything a probe.
Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2 ↗