Unknown

Dataset Information

0

Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response.


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 (AC50 = 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.

SUBMITTER: Flaherty DP 

PROVIDER: S-EPMC4266338 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC6102046 | biostudies-literature
| S-EPMC7005498 | biostudies-literature
| S-EPMC5986218 | biostudies-literature
| S-EPMC4645248 | biostudies-literature
| S-EPMC3956512 | biostudies-literature
| S-EPMC6484020 | biostudies-literature
| S-EPMC2787632 | biostudies-literature
| S-EPMC4428047 | biostudies-literature
| S-EPMC9426425 | biostudies-literature
| S-EPMC3388238 | biostudies-literature