KZR-8445 (KZR8445) is a cyclic depsipeptide, client-selective Sec61 inhibitor with IC50 of 100 nM, targets the Sec61 translocon and selectively modulate Sec61-mediated protein biogenesis.
KZR-8445 binds to the central region of the Sec61 lateral gate in an open configuration, with direct contacts to the lumenal plug.
KZR8445 blocks CoV-2 replication and virus-induced cytotoxicity in Vero cells, an effect that is likely mediated by inhibition of spike protein biogenesis.
KZR8445 could overcome dexamethasone resistance in T-cell acute lymphoblastic leukemia cells in vitro.
KZR-8445 potently inhibits the secretion of proinflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis.
KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer.