Cascade DEL turns weak Pin1 fragments into covalent inhibitors
- A cascade DNA-encoded library workflow starts with photo-crosslinking selection to capture weakly binding fragments of the isomerase Pin1.
- Those fragments seed covalent-focused libraries, which are screened again for compounds that modify Cys113 on the enzyme.
- Two covalent hits showed potent inhibition, suggesting fragments can be evolved into covalent leads without a pre-existing affinity scaffold.
💡 Points Based on the abstract
A cysteine-directed route that sidesteps the pSer/Thr pocket is appealing if phosphate-mimetic ligands raise permeability concerns, though that depends on the paper's own data. Not in the summary: kinact/KI rather than a bare potency claim, intact-protein MS for stoichiometry, a Cys113Ala control and proteome-wide selectivity. Whether fragment-derived warheads are selective or merely reactive is the question to answer.