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Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer
Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein intera...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750927/ https://www.ncbi.nlm.nih.gov/pubmed/31555737 http://dx.doi.org/10.1126/sciadv.aax2277 |
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author | Wang, Lei Zhang, Lixiao Li, Li Jiang, Jingsheng Zheng, Zhen Shang, Jialin Wang, Chengxiang Chen, Weilin Bao, Qichao Xu, Xiaoli Jiang, Zhengyu Zhang, Jian You, Qidong |
author_facet | Wang, Lei Zhang, Lixiao Li, Li Jiang, Jingsheng Zheng, Zhen Shang, Jialin Wang, Chengxiang Chen, Weilin Bao, Qichao Xu, Xiaoli Jiang, Zhengyu Zhang, Jian You, Qidong |
author_sort | Wang, Lei |
collection | PubMed |
description | Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu(47), one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy. |
format | Online Article Text |
id | pubmed-6750927 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-67509272019-09-25 Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer Wang, Lei Zhang, Lixiao Li, Li Jiang, Jingsheng Zheng, Zhen Shang, Jialin Wang, Chengxiang Chen, Weilin Bao, Qichao Xu, Xiaoli Jiang, Zhengyu Zhang, Jian You, Qidong Sci Adv Research Articles Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu(47), one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy. American Association for the Advancement of Science 2019-09-18 /pmc/articles/PMC6750927/ /pubmed/31555737 http://dx.doi.org/10.1126/sciadv.aax2277 Text en Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Wang, Lei Zhang, Lixiao Li, Li Jiang, Jingsheng Zheng, Zhen Shang, Jialin Wang, Chengxiang Chen, Weilin Bao, Qichao Xu, Xiaoli Jiang, Zhengyu Zhang, Jian You, Qidong Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer |
title | Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer |
title_full | Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer |
title_fullStr | Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer |
title_full_unstemmed | Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer |
title_short | Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer |
title_sort | small-molecule inhibitor targeting the hsp90-cdc37 protein-protein interaction in colorectal cancer |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750927/ https://www.ncbi.nlm.nih.gov/pubmed/31555737 http://dx.doi.org/10.1126/sciadv.aax2277 |
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