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Suppression of the ubiquitin pathway by small molecule binding to ubiquitin enhances doxorubicin sensitivity of the cancer cells

Suppression of the ubiquitin pathway by small molecule binding to ubiquitin enhances doxorubicin sensitivity of the cancer cells
Suppression of the ubiquitin pathway by small molecule binding to ubiquitin enhances doxorubicin sensitivity of the cancer cells
Development of inhibitors for ubiquitin pathway has been suggested as a promising strategy to treat several types of cancers, which has been showcased by recent success of a series of novel anticancer drugs based on inhibition of ubiquitin pathways. Although the druggability of enzymes in ubiquitin pathways has been demonstrated, ubiquitin itself, the main agent of the pathway, has not been targeted. Whereas conventional enzyme inhibitors are used to silence the ubiquitination or reverse it, they cannot disrupt the binding activity of ubiquitin. Herein, we report that the scaffolds of sulfonated aryl diazo compounds, particularly Congo red, could disrupt the binding activity of ubiquitin, resulting in the activity equivalent to inhibition of ubiquitination. NMR mapping assay demonstrated that the chemical directly binds to the recognition site for ubiquitin processing enzymes on the surface of ubiquitin, and thereby blocks the binding of ubiquitin to its cognate receptors. As a proof of concept for the druggability of the ubiquitin molecule, we demonstrated that Congo red acted as an intracellular inhibitor of ubiquitin recognition and binding, which led to inhibition of ubiquitination, and thereby, could be used as a sensitizer for conventional anticancer drugs, doxorubicin.
1420-3049
Nguyen, Thanh
f71be1c4-c647-4229-bb13-d8dc90d5e527
Ho, Minh
7aef5224-9488-4baa-8a1f-7cc636654f49
Kim, Kyungmin
a83853a8-df9d-4b96-8a5e-76807efe9231
Yun, Sun-Il
de6b49a3-c4df-4397-af27-6b1e93a69eb4
Mizar, Pushpak
631b688c-b7fb-41d7-8038-9fb48ef935c7
Easton, James W.
f25ce1dd-f00c-4a84-b773-9ef229b22350
Lee, Seung Seo
ee34fa26-5fb6-48c8-80c2-1f13ec4ccceb
Kim, Kyeong Kyu
a7757cb7-065e-4e76-a669-27d2108bef97
Nguyen, Thanh
f71be1c4-c647-4229-bb13-d8dc90d5e527
Ho, Minh
7aef5224-9488-4baa-8a1f-7cc636654f49
Kim, Kyungmin
a83853a8-df9d-4b96-8a5e-76807efe9231
Yun, Sun-Il
de6b49a3-c4df-4397-af27-6b1e93a69eb4
Mizar, Pushpak
631b688c-b7fb-41d7-8038-9fb48ef935c7
Easton, James W.
f25ce1dd-f00c-4a84-b773-9ef229b22350
Lee, Seung Seo
ee34fa26-5fb6-48c8-80c2-1f13ec4ccceb
Kim, Kyeong Kyu
a7757cb7-065e-4e76-a669-27d2108bef97

Nguyen, Thanh, Ho, Minh, Kim, Kyungmin, Yun, Sun-Il, Mizar, Pushpak, Easton, James W., Lee, Seung Seo and Kim, Kyeong Kyu (2019) Suppression of the ubiquitin pathway by small molecule binding to ubiquitin enhances doxorubicin sensitivity of the cancer cells. Molecules, 24 (6). (doi:10.3390/molecules24061073).

Record type: Article

Abstract

Development of inhibitors for ubiquitin pathway has been suggested as a promising strategy to treat several types of cancers, which has been showcased by recent success of a series of novel anticancer drugs based on inhibition of ubiquitin pathways. Although the druggability of enzymes in ubiquitin pathways has been demonstrated, ubiquitin itself, the main agent of the pathway, has not been targeted. Whereas conventional enzyme inhibitors are used to silence the ubiquitination or reverse it, they cannot disrupt the binding activity of ubiquitin. Herein, we report that the scaffolds of sulfonated aryl diazo compounds, particularly Congo red, could disrupt the binding activity of ubiquitin, resulting in the activity equivalent to inhibition of ubiquitination. NMR mapping assay demonstrated that the chemical directly binds to the recognition site for ubiquitin processing enzymes on the surface of ubiquitin, and thereby blocks the binding of ubiquitin to its cognate receptors. As a proof of concept for the druggability of the ubiquitin molecule, we demonstrated that Congo red acted as an intracellular inhibitor of ubiquitin recognition and binding, which led to inhibition of ubiquitination, and thereby, could be used as a sensitizer for conventional anticancer drugs, doxorubicin.

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Accepted/In Press date: 14 March 2019
Published date: 19 March 2019

Identifiers

Local EPrints ID: 429245
URI: https://eprints.soton.ac.uk/id/eprint/429245
ISSN: 1420-3049
PURE UUID: 753219a7-e341-40c4-9193-cda01857951f
ORCID for Seung Seo Lee: ORCID iD orcid.org/0000-0002-8598-3303

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Date deposited: 25 Mar 2019 17:30
Last modified: 26 Mar 2019 01:30

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Contributors

Author: Thanh Nguyen
Author: Minh Ho
Author: Kyungmin Kim
Author: Sun-Il Yun
Author: Pushpak Mizar
Author: James W. Easton
Author: Seung Seo Lee ORCID iD
Author: Kyeong Kyu Kim

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