1 research outputs found
Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response
Cellular proteins that fail to fold
properly result in inactive
or disfunctional proteins that can have toxic functions. The unfolded
protein response (UPR) is a two-tiered cellular mechanism initiated
by eukaryotic cells that have accumulated misfolded proteins within
the endoplasmic reticulum (ER). An adaptive pathway facilitates the
clearance of the undesired proteins; however, if overwhelmed, cells
trigger apoptosis by upregulating transcription factors such as C/EBP-homologous
protein (CHOP). A high throughput screen was performed directed at
identifying compounds that selectively upregulate the apoptotic CHOP
pathway while avoiding adaptive signaling cascades, resulting in a
sulfonamidebenzamide chemotype that was optimized. These efforts produced
a potent and selective CHOP inducer (AC<sub>50</sub> = 0.8 μM;
XBP1 > 80 μM), which was efficacious in both mouse embryonic
fibroblast cells and a human oral squamous cell cancer cell line,
and demonstrated antiproliferative effects for multiple cancer cell
lines in the NCI-60 panel