Lysine-Targeted Covalent Fragments Open a New Allosteric Route to Inhibit SHP2
- Researchers built a combined screening pipeline pairing covalent fragment screening with a ligand-first design strategy to find chemical matter that reacts with lysine side chains rather than the more commonly targeted cysteines.
- The work focuses on the allosteric "latch" region of SHP2 phosphatase, a regulatory site distinct from the enzyme's catalytic pocket and from previously drugged allosteric tunnel sites.
- Computational modeling and experimental characterization were used together to guide fragment selection and to understand how covalent attachment at latch-site lysines affects the protein's conformational behavior.
- The approach yielded inhibitors described as the first potent, cell-active covalent compounds acting through this latch site, indicating the pocket can support functional, drug-like engagement rather than only structural characterization.
- The findings position lysine-directed covalent chemistry as a viable route for allosteric SHP2 modulation and provide a starting chemotype and site for further medicinal chemistry optimization.
Lysine-directed covalency is the real bet here, more than the new pocket itself: warhead chemistry and selectivity triage are far less mature than for cysteine acrylamides, so the first thing I'd pull up is proteome-wide lysine reactivity data before trusting the cell activity. The latch site itself is also genuinely new — it sits apart from where SHP099/TNO155-type allosteric inhibitors already bind, so this isn't retreading crowded IP. Getting cell-active hits straight out of fragment screening is a strong signal for this pocket's shape or a hyperreactive lysine — but fragment-to-lead on Lys chemistry means slower SAR cycles than we're used to with Cys warheads. Real value: a fresh chemotype and site for a target whose allosteric space was starting to feel exhausted.
Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2 ↗