Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell
Gankyrin is an ankyrin-repeat oncoprotein whose overexpression has been implicated in the development of many cancer types. Elevated gankyrin levels are linked to aberrant cellular events including enhanced degradation of tumour suppressor protein p53, and inhibition of gankyrin activity has therefo...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/80807 http://hdl.handle.net/10220/46601 |
| _version_ | 1811677272301633536 |
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| author | Chattopadhyay, Anasuya O’Connor, Cornelius J. Zhang, Fengzhi Galvagnion, Celine Galloway, Warren R. J. D. Tan, Yaw Sing Stokes, Jamie E. Rahman, Taufiq Verma, Chandra Spring, David R. Itzhaki, Laura S. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Chattopadhyay, Anasuya O’Connor, Cornelius J. Zhang, Fengzhi Galvagnion, Celine Galloway, Warren R. J. D. Tan, Yaw Sing Stokes, Jamie E. Rahman, Taufiq Verma, Chandra Spring, David R. Itzhaki, Laura S. |
| author_sort | Chattopadhyay, Anasuya |
| collection | NTU |
| description | Gankyrin is an ankyrin-repeat oncoprotein whose overexpression has been implicated in the development of many cancer types. Elevated gankyrin levels are linked to aberrant cellular events including enhanced degradation of tumour suppressor protein p53, and inhibition of gankyrin activity has therefore been identified as an attractive anticancer strategy. Gankyrin interacts with several partner proteins, and a number of these protein-protein interactions (PPIs) are of relevance to cancer. Thus, molecules that bind the PPI interface of gankyrin and interrupt these interactions are of considerable interest. Herein, we report the discovery of a small molecule termed cjoc42 that is capable of binding to gankyrin. Cell-based experiments demonstrate that cjoc42 can inhibit gankyrin activity in a dose-dependent manner: cjoc42 prevents the decrease in p53 protein levels normally associated with high amounts of gankyrin, and it restores p53-dependent transcription and sensitivity to DNA damage. The results represent the first evidence that gankyrin is a “druggable” target with small molecules. |
| first_indexed | 2024-10-01T02:34:44Z |
| format | Journal Article |
| id | ntu-10356/80807 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:34:44Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/808072023-02-28T16:59:53Z Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell Chattopadhyay, Anasuya O’Connor, Cornelius J. Zhang, Fengzhi Galvagnion, Celine Galloway, Warren R. J. D. Tan, Yaw Sing Stokes, Jamie E. Rahman, Taufiq Verma, Chandra Spring, David R. Itzhaki, Laura S. School of Biological Sciences DNA Damage DRNTU::Science::Biological sciences Cell Cycle Protein Gankyrin is an ankyrin-repeat oncoprotein whose overexpression has been implicated in the development of many cancer types. Elevated gankyrin levels are linked to aberrant cellular events including enhanced degradation of tumour suppressor protein p53, and inhibition of gankyrin activity has therefore been identified as an attractive anticancer strategy. Gankyrin interacts with several partner proteins, and a number of these protein-protein interactions (PPIs) are of relevance to cancer. Thus, molecules that bind the PPI interface of gankyrin and interrupt these interactions are of considerable interest. Herein, we report the discovery of a small molecule termed cjoc42 that is capable of binding to gankyrin. Cell-based experiments demonstrate that cjoc42 can inhibit gankyrin activity in a dose-dependent manner: cjoc42 prevents the decrease in p53 protein levels normally associated with high amounts of gankyrin, and it restores p53-dependent transcription and sensitivity to DNA damage. The results represent the first evidence that gankyrin is a “druggable” target with small molecules. Published version 2018-11-08T04:50:36Z 2019-12-06T13:59:23Z 2018-11-08T04:50:36Z 2019-12-06T13:59:23Z 2016 Journal Article Chattopadhyay, A., O’Connor, C. J., Zhang, F., Galvagnion, C., Galloway, W. R. J. D., Tan, Y. S., . . . Itzhaki, L. S. (2016). Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell. Scientific Reports, 6, 23732-. doi:10.1038/srep23732 https://hdl.handle.net/10356/80807 http://hdl.handle.net/10220/46601 10.1038/srep23732 27046077 en Scientific Reports © 2016 The Authors (Nature Publishing Group). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ 11 p. application/pdf |
| spellingShingle | DNA Damage DRNTU::Science::Biological sciences Cell Cycle Protein Chattopadhyay, Anasuya O’Connor, Cornelius J. Zhang, Fengzhi Galvagnion, Celine Galloway, Warren R. J. D. Tan, Yaw Sing Stokes, Jamie E. Rahman, Taufiq Verma, Chandra Spring, David R. Itzhaki, Laura S. Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell |
| title | Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell |
| title_full | Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell |
| title_fullStr | Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell |
| title_full_unstemmed | Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell |
| title_short | Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell |
| title_sort | discovery of a small molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell |
| topic | DNA Damage DRNTU::Science::Biological sciences Cell Cycle Protein |
| url | https://hdl.handle.net/10356/80807 http://hdl.handle.net/10220/46601 |
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