Ritterostatin GN1N, a Cephalostatin–Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78

Andrew J. Ambrose, Evelyne A. Santos, Paula C. Jimenez, Danilo D. Rocha, Diego V. Wilke, Paolo Beuzer, Josh Axelrod, Ananda Kumar Kanduluru, Philip L. Fuchs, Hu Cang, Letícia V. Costa-Lotufo, Eli Chapman, James J. La Clair

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Natural products discovered by using agnostic approaches, unlike rationally designed leads or those obtained through high-throughput screening, offer the ability to reveal new biological pathways and, hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine–cephalostatin family of natural products displays robust and potent antitumor activities, with sub-nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we used comparative cellular and molecular biological methods to uncover the ritterazine–cephalostatin cytotoxic mode of action (MOA) in human tumor cells. Our findings indicated that, whereas ritterostatin GN1N, a cephalostatin–ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER)-based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death.

Original languageEnglish (US)
Pages (from-to)506-510
Number of pages5
JournalChemBioChem
Volume18
Issue number6
DOIs
StatePublished - Mar 16 2017

Keywords

  • cephalostatin
  • drug discovery
  • GRP78
  • natural products
  • ritterazine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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    Ambrose, A. J., Santos, E. A., Jimenez, P. C., Rocha, D. D., Wilke, D. V., Beuzer, P., Axelrod, J., Kumar Kanduluru, A., Fuchs, P. L., Cang, H., Costa-Lotufo, L. V., Chapman, E., & La Clair, J. J. (2017). Ritterostatin GN1N, a Cephalostatin–Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78. ChemBioChem, 18(6), 506-510. https://doi.org/10.1002/cbic.201600669