Document Report Card

ID: ALA3352780

Journal: ACS Med Chem Lett

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

Authors: Flaherty DP, Miller JR, Garshott DM, Hedrick M, Gosalia P, Li Y, Milewski M, Sugarman E, Vasile S, Salaniwal S, Su Y, Smith LH, Chung TD, Pinkerton AB, Aubé J, Callaghan MU, Golden JE, Fribley AM, Kaufman RJ.

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.

CiteXplore: 25530830

DOI: 10.1021/ml5003234