Direct-to-Biology Screening Yields a GRP78 Inhibitor That Spares Other HSP70 Isoforms
- Isoform selectivity within the highly conserved HSP70 family is notoriously hard; the team targeted the peptide-binding pocket of GRP78's substrate-binding domain.
- A direct-to-biology workflow, testing crude library reactions without purification, pointed to compound 12.
- It engages GRP78 in biochemical, biophysical and cellular thermal shift assays, is selective over other tested HSP70s, and perturbs unfolded protein response signaling with selective killing of A549 cells.
💡 Points
Going after the substrate pocket rather than the ATP site is the sensible way to buy HSP70 selectivity, and D2B makes iterating on it cheap. The cell-line-selective killing is the part I'd treat cautiously: it could reflect UPR dependence or something off-target. Orthogonal engagement data like CETSA are encouraging; I'd want a close inactive analog next.
Development of Isoform-Selective GRP78 Inhibitors from a Direct-to-Biology Strategy ↗