2. Academic Validation
  3. Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response

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

  • ACS Med Chem Lett. 2014 Oct 29;5(12):1278-1283. doi: 10.1021/ml5003234.
Daniel P Flaherty 1,  Justin R Miller 2,  Danielle M Garshott 2,  Michael Hedrick 3,  Palak Gosalia 3,  Yujie Li 3,  Monika Milewski 3,  Eliot Sugarman 4,  Stefan Vasile 4,  Sumeet Salaniwal 3,  Ying Su 3,  Layton H Smith 4,  Thomas D Y Chung 3,  Anthony B Pinkerton 3,  Jeffrey Aubé 1,  Michael U Callaghan 2,  Jennifer E Golden 1,  Andrew M Fribley 2,  Randal J Kaufman 5
Affiliations

Affiliations

  • 1 Delbert M. Shankel Structural Biology Center, University of Kansas Specialized Chemistry Center , 2034 Becker Drive, Lawrence, Kansas 66047, United States.
  • 2 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.
  • 3 Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , La Jolla, California 92037, United States.
  • 4 Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute at Lake Nona , Orlando, Florida 32827, United States.
  • 5 Program in Degenerative Disease Research, Sanford-Burnham Medical Research Institute , 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
PMID: 25530830 DOI: 10.1021/ml5003234
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.

Keywords

CHOP activator; UPR apoptotic pathway activator; UPR modulator; anticancer.

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