Discovery of Sulfonamidebenzamides as Selective Apoptotic
CHOP Pathway Activators of the Unfolded Protein Response
- Publication date
- Publisher
Abstract
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