Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo antitumor activity

Tara L. Peters, Joseph Tillotson, Alison M. Yeomans, Sarah Wilmore, Elizabeth Lemm, Carlos Jimenez-Romero, Luis A. Amador, Lingxiao Li, Amit D. Amin, Praechompoo Pongtornpipat, Christopher J. Zerio, Andrew J. Ambrose, Gillian Paine-Murrieta, Patricia Greninger, Francisco Vega, Cyril H. Benes, Graham Packham, Abimael D. Rodríguez, Eli Chapman, Jonathan H Schatz

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors. Experimental Design: We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding site muta-genesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors. Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at approximately 100 relative dosing, leading to significant activity against lymphoma xenografts. Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo antitumor activities provides proof of principle for target-based screening against this highly promising target for cancer therapy.

Original languageEnglish (US)
Pages (from-to)4256-4270
Number of pages15
JournalClinical Cancer Research
Volume24
Issue number17
DOIs
StatePublished - Sep 1 2018

Fingerprint

Biological Products
Neoplasms
DEAD-box RNA Helicases
Heterografts
Adenosine Triphosphatases
Lymphoma
Hydrolysis
Research Design
Adenosine Triphosphate
Binding Sites
elatol
Apoptosis
Drug Therapy
Growth
Proteins
In Vitro Techniques
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo antitumor activity. / Peters, Tara L.; Tillotson, Joseph; Yeomans, Alison M.; Wilmore, Sarah; Lemm, Elizabeth; Jimenez-Romero, Carlos; Amador, Luis A.; Li, Lingxiao; Amin, Amit D.; Pongtornpipat, Praechompoo; Zerio, Christopher J.; Ambrose, Andrew J.; Paine-Murrieta, Gillian; Greninger, Patricia; Vega, Francisco; Benes, Cyril H.; Packham, Graham; Rodríguez, Abimael D.; Chapman, Eli; Schatz, Jonathan H.

In: Clinical Cancer Research, Vol. 24, No. 17, 01.09.2018, p. 4256-4270.

Research output: Contribution to journalArticle

Peters, TL, Tillotson, J, Yeomans, AM, Wilmore, S, Lemm, E, Jimenez-Romero, C, Amador, LA, Li, L, Amin, AD, Pongtornpipat, P, Zerio, CJ, Ambrose, AJ, Paine-Murrieta, G, Greninger, P, Vega, F, Benes, CH, Packham, G, Rodríguez, AD, Chapman, E & Schatz, JH 2018, 'Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo antitumor activity', Clinical Cancer Research, vol. 24, no. 17, pp. 4256-4270. https://doi.org/10.1158/1078-0432.CCR-17-3645
Peters, Tara L. ; Tillotson, Joseph ; Yeomans, Alison M. ; Wilmore, Sarah ; Lemm, Elizabeth ; Jimenez-Romero, Carlos ; Amador, Luis A. ; Li, Lingxiao ; Amin, Amit D. ; Pongtornpipat, Praechompoo ; Zerio, Christopher J. ; Ambrose, Andrew J. ; Paine-Murrieta, Gillian ; Greninger, Patricia ; Vega, Francisco ; Benes, Cyril H. ; Packham, Graham ; Rodríguez, Abimael D. ; Chapman, Eli ; Schatz, Jonathan H. / Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo antitumor activity. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 17. pp. 4256-4270.
@article{9c1e55432d7c4ffb8751eec0bddefa18,
title = "Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo antitumor activity",
abstract = "Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors. Experimental Design: We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding site muta-genesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors. Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at approximately 100 relative dosing, leading to significant activity against lymphoma xenografts. Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo antitumor activities provides proof of principle for target-based screening against this highly promising target for cancer therapy.",
author = "Peters, {Tara L.} and Joseph Tillotson and Yeomans, {Alison M.} and Sarah Wilmore and Elizabeth Lemm and Carlos Jimenez-Romero and Amador, {Luis A.} and Lingxiao Li and Amin, {Amit D.} and Praechompoo Pongtornpipat and Zerio, {Christopher J.} and Ambrose, {Andrew J.} and Gillian Paine-Murrieta and Patricia Greninger and Francisco Vega and Benes, {Cyril H.} and Graham Packham and Rodr{\'i}guez, {Abimael D.} and Eli Chapman and Schatz, {Jonathan H}",
year = "2018",
month = "9",
day = "1",
doi = "10.1158/1078-0432.CCR-17-3645",
language = "English (US)",
volume = "24",
pages = "4256--4270",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "17",

}

TY - JOUR

T1 - Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo antitumor activity

AU - Peters, Tara L.

AU - Tillotson, Joseph

AU - Yeomans, Alison M.

AU - Wilmore, Sarah

AU - Lemm, Elizabeth

AU - Jimenez-Romero, Carlos

AU - Amador, Luis A.

AU - Li, Lingxiao

AU - Amin, Amit D.

AU - Pongtornpipat, Praechompoo

AU - Zerio, Christopher J.

AU - Ambrose, Andrew J.

AU - Paine-Murrieta, Gillian

AU - Greninger, Patricia

AU - Vega, Francisco

AU - Benes, Cyril H.

AU - Packham, Graham

AU - Rodríguez, Abimael D.

AU - Chapman, Eli

AU - Schatz, Jonathan H

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors. Experimental Design: We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding site muta-genesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors. Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at approximately 100 relative dosing, leading to significant activity against lymphoma xenografts. Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo antitumor activities provides proof of principle for target-based screening against this highly promising target for cancer therapy.

AB - Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors. Experimental Design: We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding site muta-genesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors. Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at approximately 100 relative dosing, leading to significant activity against lymphoma xenografts. Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo antitumor activities provides proof of principle for target-based screening against this highly promising target for cancer therapy.

UR - http://www.scopus.com/inward/record.url?scp=85052744579&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052744579&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-17-3645

DO - 10.1158/1078-0432.CCR-17-3645

M3 - Article

VL - 24

SP - 4256

EP - 4270

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 17

ER -