Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy
Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N−ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate...
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MDPI AG
2022-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/17/5561 |
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| author | Xin Pan Teng-yu Mao Yan-wen Mai Cheng-cheng Liang Wei-hao Huang Yong Rao Zhi-shu Huang Shi-liang Huang |
| author_facet | Xin Pan Teng-yu Mao Yan-wen Mai Cheng-cheng Liang Wei-hao Huang Yong Rao Zhi-shu Huang Shi-liang Huang |
| author_sort | Xin Pan |
| collection | DOAJ |
| description | Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N−ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual−target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N−ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug−resistant cell line MCF−7/ADR and the atypical drug−resistant tumor cell line HL−60/MX2. Our study identified quinacrine as a potential dual−target inhibitor of Topo II and Hsp90, depending on the ATP−binding domain, positioning it as a hit compound for further structural modification. |
| first_indexed | 2024-03-10T01:30:07Z |
| format | Article |
| id | doaj.art-d57ae07bd94249d987c71b314455d0d3 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T01:30:07Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-d57ae07bd94249d987c71b314455d0d32023-11-23T13:44:07ZengMDPI AGMolecules1420-30492022-08-012717556110.3390/molecules27175561Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer TherapyXin Pan0Teng-yu Mao1Yan-wen Mai2Cheng-cheng Liang3Wei-hao Huang4Yong Rao5Zhi-shu Huang6Shi-liang Huang7School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaTopo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N−ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual−target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N−ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug−resistant cell line MCF−7/ADR and the atypical drug−resistant tumor cell line HL−60/MX2. Our study identified quinacrine as a potential dual−target inhibitor of Topo II and Hsp90, depending on the ATP−binding domain, positioning it as a hit compound for further structural modification.https://www.mdpi.com/1420-3049/27/17/5561HSP90 inhibitordual−target inhibitortopo II inhibitorquinacrinethe N−ATPase domains |
| spellingShingle | Xin Pan Teng-yu Mao Yan-wen Mai Cheng-cheng Liang Wei-hao Huang Yong Rao Zhi-shu Huang Shi-liang Huang Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy Molecules HSP90 inhibitor dual−target inhibitor topo II inhibitor quinacrine the N−ATPase domains |
| title | Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy |
| title_full | Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy |
| title_fullStr | Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy |
| title_full_unstemmed | Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy |
| title_short | Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy |
| title_sort | discovery of quinacrine as a potent topo ii and hsp90 dual target inhibitor repurposing for cancer therapy |
| topic | HSP90 inhibitor dual−target inhibitor topo II inhibitor quinacrine the N−ATPase domains |
| url | https://www.mdpi.com/1420-3049/27/17/5561 |
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