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