Design, Synthesis, and Biological Evaluation of Novel Allosteric Protein Disulfide Isomerase Inhibitors Suhui Yang Andrea Shergalis Dan Lu Anahita Kyani Ziwei Liu Mats Ljungman Nouri Neamati 10.1021/acs.jmedchem.8b01951.s009 https://acs.figshare.com/articles/dataset/Design_Synthesis_and_Biological_Evaluation_of_Novel_Allosteric_Protein_Disulfide_Isomerase_Inhibitors/7940663 Protein disulfide isomerase (PDI) is responsible for nascent protein folding in the endoplasmic reticulum (ER) and is critical for glioblastoma survival. To improve the potency of lead PDI inhibitor <b>BAP2</b> ((<i>E</i>)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)­benzonitrile), we designed and synthesized 67 analogues. We determined that PDI inhibition relied on the A ring hydroxyl group of the chalcone scaffold and cLogP increase in the sulfonamide chain improved potency. Docking studies revealed that <b>BAP2</b> and analogues bind to His256 in the b′ domain of PDI, and mutation of His256 to Ala abolishes <b>BAP2</b> analogue activity. <b>BAP2</b> and optimized analogue <b>59</b> have modest thiol reactivity; however, we propose that PDI inhibition by <b>BAP2</b> analogues depends on the b′ domain. Importantly, analogues inhibit glioblastoma cell growth, induce ER stress, increase expression of G2M checkpoint proteins, and reduce expression of DNA repair proteins. Cumulatively, our results support inhibition of PDI as a novel strategy to treat glioblastoma. 2019-02-13 00:00:00 optimized analogue 59 Ala abolishes BAP 2 analogue activity Novel Allosteric Protein Disulfide Isomerase Inhibitors Protein disulfide isomerase results support inhibition glioblastoma cell growth ring hydroxyl group ER DNA repair proteins G 2M checkpoint proteins BAP 2 analogues PDI inhibition BAP 2