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

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

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.

1078-0432
4256-4270
Peters, Tara L.
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Tillotson, Joseph
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Yeomans, Alison M.
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Wilmore, Sarah
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Lemm, Elizabeth
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Jimenez-Romero, Carlos
2be5b19f-cbcf-42b4-bc06-5798149a64f8
Amador, Luis A.
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Li, Lingxiao
d9e0cd95-88f5-4183-8deb-742e43104462
Amin, Amit D.
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Pongtornpipat, Praechompoo
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Zerio, Christopher J.
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Ambrose, Andrew J.
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Paine-Murrieta, Gillian
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Greninger, Patricia
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Vega, Francisco
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Benes, Cyril H.
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Packham, Graham
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Rodríguez, Abimael D.
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Chapman, Eli
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Schatz, Jonathan H.
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Peters, Tara L.
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Tillotson, Joseph
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Yeomans, Alison M.
b47f0dfe-596f-4cef-b4b6-2233b7cdd899
Wilmore, Sarah
b3ae1360-0c10-440b-87d1-e9be4d1c326e
Lemm, Elizabeth
3db962f5-4499-41fb-a491-bc558b5f45df
Jimenez-Romero, Carlos
2be5b19f-cbcf-42b4-bc06-5798149a64f8
Amador, Luis A.
9a9d7652-4154-4f52-a9a6-454ca93cf465
Li, Lingxiao
d9e0cd95-88f5-4183-8deb-742e43104462
Amin, Amit D.
224c88e0-9cf8-4b41-a01f-c50206c259b8
Pongtornpipat, Praechompoo
f9606a1f-4afd-45ea-a31c-80b39f5a7998
Zerio, Christopher J.
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Ambrose, Andrew J.
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Paine-Murrieta, Gillian
ea5968da-f313-48be-a48d-3729c8dbb86e
Greninger, Patricia
3d996e32-d21f-4dff-8c42-a6de678171a1
Vega, Francisco
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Benes, Cyril H.
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Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Rodríguez, Abimael D.
d7850619-31f6-48c4-9b40-dfe5f4107675
Chapman, Eli
3d3d0e50-00e7-485c-9613-c1b244dba6ad
Schatz, Jonathan H.
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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 and Schatz, Jonathan H. (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, 24 (17), 4256-4270. (doi:10.1158/1078-0432.CCR-17-3645).

Record type: Article

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.

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Peters-Schatz Combined Resubmission - Accepted Manuscript
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Accepted/In Press date: 21 May 2018
e-pub ahead of print date: 29 May 2018
Published date: 1 September 2018

Identifiers

Local EPrints ID: 423285
URI: https://eprints.soton.ac.uk/id/eprint/423285
ISSN: 1078-0432
PURE UUID: 500ffa4a-f660-4d3c-ad27-ead0c006729c
ORCID for Sarah Wilmore: ORCID iD orcid.org/0000-0002-6929-0267
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 20 Sep 2018 16:30
Last modified: 14 Mar 2019 05:03

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Contributors

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

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