title: 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.
authors.affiliation: Delbert M. Shankel Structural Biology Center, University of Kansas Specialized Chemistry Center , 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Flaherty
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Division of Hematology and Oncology, and the Karmanos Cancer Institute Molecular Therapeutics Group, Wayne State University , 2228 Elliman Building, 421 East Canfield, Detroit, Michigan 48201, United States.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Miller
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Division of Hematology and Oncology, and the Karmanos Cancer Institute Molecular Therapeutics Group, Wayne State University , 2228 Elliman Building, 421 East Canfield, Detroit, Michigan 48201, United States.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Garshott
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Hedrick
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Palak
authors.initials: P
authors.lastname: Gosalia
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Monika
authors.initials: M
authors.lastname: Milewski
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute at Lake Nona , Orlando, Florida 32827, United States.
authors.forename: Eliot
authors.initials: E
authors.lastname: Sugarman
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute at Lake Nona , Orlando, Florida 32827, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Salaniwal
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute at Lake Nona , Orlando, Florida 32827, United States.
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Thomas D Y
authors.initials: TD
authors.lastname: Chung
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: Delbert M. Shankel Structural Biology Center, University of Kansas Specialized Chemistry Center , 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Division of Hematology and Oncology, and the Karmanos Cancer Institute Molecular Therapeutics Group, Wayne State University , 2228 Elliman Building, 421 East Canfield, Detroit, Michigan 48201, United States.
authors.forename: Michael U
authors.initials: MU
authors.lastname: Callaghan
authors.affiliation: Delbert M. Shankel Structural Biology Center, University of Kansas Specialized Chemistry Center , 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Golden
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Division of Hematology and Oncology, and the Karmanos Cancer Institute Molecular Therapeutics Group, Wayne State University , 2228 Elliman Building, 421 East Canfield, Detroit, Michigan 48201, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fribley
authors.affiliation: Program in Degenerative Disease Research, Sanford-Burnham Medical Research Institute , 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
keywords: CHOP activator; UPR apoptotic pathway activator; UPR modulator; anticancer