E64FC65

E64FC65 is a small molecule indene-based inhibitor specifically targeting the 'a' domain of Protein Disulfide Isomerase A1 (PDIA1). Developed by researchers at the Medical University of South Carolina, it is an advanced derivative of the pan-PDI inhibitor E64FC26. E64FC65 exhibits high selectivity for PDIA1 over other isoforms such as PDIA3, PDIA4, PDIA6, and TXNDC5. In multiple myeloma models, inhibition of PDIA1 by E64FC65 induces endoplasmic reticulum (ER) and oxidative stress, leading to the accumulation of misfolded poly-ubiquitinated proteins and activation of the unfolded protein response (UPR) biomarkers ATF4, CHOP, and Nrf2. It has been shown to significantly potentiate the cytotoxic effects of proteasome inhibitors like bortezomib while demonstrating reduced toxicity toward normal cells, such as primary human T-cells, and improved pharmaceutical properties in ADME assays.