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

6 Citations (Scopus)

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

Fingerprint

Pyrazines
Biological Products
Cells
Unfolded Protein Response
Cell death
Drug Discovery
Heterografts
Endoplasmic Reticulum
Tumors
Screening
Protein Isoforms
Cell Death
Chemical activation
Throughput
Cell Line
Growth
Neoplasms
Proteins

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Cite this

Ambrose, A. J., Santos, E. A., Jimenez, P. C., Rocha, D. D., Wilke, D. V., Beuzer, P., ... 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

Ritterostatin GN1N, a Cephalostatin–Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78. / Ambrose, Andrew J.; Santos, Evelyne A.; Jimenez, Paula C.; Rocha, Danilo D.; Wilke, Diego V.; Beuzer, Paolo; Axelrod, Josh; Kumar Kanduluru, Ananda; Fuchs, Philip L.; Cang, Hu; Costa-Lotufo, Letícia V.; Chapman, Eli; La Clair, James J.

In: ChemBioChem, Vol. 18, No. 6, 16.03.2017, p. 506-510.

Research output: Contribution to journalArticle

Ambrose, AJ, Santos, EA, Jimenez, PC, Rocha, DD, Wilke, DV, Beuzer, P, Axelrod, J, Kumar Kanduluru, A, Fuchs, PL, Cang, H, Costa-Lotufo, LV, Chapman, E & La Clair, JJ 2017, 'Ritterostatin GN1N, a Cephalostatin–Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78', ChemBioChem, vol. 18, no. 6, pp. 506-510. https://doi.org/10.1002/cbic.201600669
Ambrose, Andrew J. ; Santos, Evelyne A. ; Jimenez, Paula C. ; Rocha, Danilo D. ; Wilke, Diego V. ; Beuzer, Paolo ; Axelrod, Josh ; Kumar Kanduluru, Ananda ; Fuchs, Philip L. ; Cang, Hu ; Costa-Lotufo, Letícia V. ; Chapman, Eli ; La Clair, James J. / Ritterostatin GN1N, a Cephalostatin–Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78. In: ChemBioChem. 2017 ; Vol. 18, No. 6. pp. 506-510.
@article{a4da86e1ac23445688627863a629915e,
title = "Ritterostatin GN1N, a Cephalostatin–Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78",
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.",
keywords = "cephalostatin, drug discovery, GRP78, natural products, ritterazine",
author = "Ambrose, {Andrew J.} and Santos, {Evelyne A.} and Jimenez, {Paula C.} and Rocha, {Danilo D.} and Wilke, {Diego V.} and Paolo Beuzer and Josh Axelrod and {Kumar Kanduluru}, Ananda and Fuchs, {Philip L.} and Hu Cang and Costa-Lotufo, {Let{\'i}cia V.} and Eli Chapman and {La Clair}, {James J.}",
year = "2017",
month = "3",
day = "16",
doi = "10.1002/cbic.201600669",
language = "English (US)",
volume = "18",
pages = "506--510",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley-VCH Verlag",
number = "6",

}

TY - JOUR

T1 - Ritterostatin GN1N, a Cephalostatin–Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78

AU - Ambrose, Andrew J.

AU - Santos, Evelyne A.

AU - Jimenez, Paula C.

AU - Rocha, Danilo D.

AU - Wilke, Diego V.

AU - Beuzer, Paolo

AU - Axelrod, Josh

AU - Kumar Kanduluru, Ananda

AU - Fuchs, Philip L.

AU - Cang, Hu

AU - Costa-Lotufo, Letícia V.

AU - Chapman, Eli

AU - La Clair, James J.

PY - 2017/3/16

Y1 - 2017/3/16

N2 - 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.

AB - 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.

KW - cephalostatin

KW - drug discovery

KW - GRP78

KW - natural products

KW - ritterazine

UR - http://www.scopus.com/inward/record.url?scp=85011718240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85011718240&partnerID=8YFLogxK

U2 - 10.1002/cbic.201600669

DO - 10.1002/cbic.201600669

M3 - Article

C2 - 28074539

AN - SCOPUS:85011718240

VL - 18

SP - 506

EP - 510

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 6

ER -