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

Daniel P Flaherty1, Justin R Miller2, Danielle M Garshott2

  • 1Delbert M. Shankel Structural Biology Center, University of Kansas Specialized Chemistry Center , 2034 Becker Drive, Lawrence, Kansas 66047, United States.

ACS Medicinal Chemistry Letters
|December 23, 2014
PubMed

Insights

Researchers identified a new compound that selectively triggers programmed cell death (apoptosis) in cancer cells by targeting the C/EBP-homologous protein (CHOP) pathway. This selective CHOP inducer shows promise for cancer therapy by promoting cancer cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Misfolded proteins in the endoplasmic reticulum (ER) trigger the unfolded protein response (UPR).
  • The UPR involves adaptive pathways for protein clearance and apoptotic pathways, including C/EBP-homologous protein (CHOP) upregulation.
  • Dysregulation of the UPR and accumulation of misfolded proteins are implicated in various diseases, including cancer.

Purpose of the Study:

  • To identify selective inducers of the apoptotic CHOP pathway within the UPR.
  • To discover novel chemical entities that can trigger cancer cell death via CHOP activation.
  • To develop potent and selective compounds for potential therapeutic applications in cancer.

Main Methods:

  • High-throughput screening to identify compounds selectively upregulating CHOP.
  • Chemical optimization of a sulfonamidebenzamide chemotype.
  • In vitro efficacy testing in mouse embryonic fibroblast cells and human oral squamous cell carcinoma lines.
  • Antiproliferative activity assessment across the NCI-60 cancer cell line panel.

Main Results:

  • A potent and selective CHOP inducer was developed with an AC50 of 0.8 μM and minimal effect on XBP1 (> 80 μM).
  • The compound demonstrated efficacy in both mouse and human cancer cell lines.
  • Significant antiproliferative effects were observed across multiple cancer cell lines in the NCI-60 panel.

Conclusions:

  • A novel sulfonamidebenzamide derivative selectively induces CHOP-mediated apoptosis.
  • This compound exhibits potent antiproliferative activity against various cancer cell lines.
  • The findings suggest potential therapeutic utility of selective CHOP inducers in cancer treatment.
Keywords:
CHOP activatorUPR apoptotic pathway activatorUPR modulatoranticancer

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