RGNCY-0084 (35G8 PDI inhibitor)

35G8 is a novel nanomolar PDI (protein disulfide isomerase) inibitor that is toxic in a panel of human glioblastoma cell lines,  PDI is overexpressed in glioblastoma and folds nascent protein responsible for the progression and spread of this brain cancer.  35G8 induces nuclear factor-like 2 (Nrf2) anti-oxidant response, endoplasmic reticulum  stress response and autophagy.  35G8 upregulates heme oxygenase 1 and solute carrier family 7 member 11 (SLC7A11) transcription and protein expression and repressed PDI target genes including thioredoxin-interacting protein 1 (TXNIP) and early growth respoinse 1 (EGFR1).  35G8 indices cell death via autophagy and ferroptosis rather than apoptosis or necrosis.  35G8 can be used as chemical probe to validate PDI as a target for brain tumor therapy.  Insulin turbidity assay IC50 = 170+10nM.