Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance
Microtubule‐targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule‐targeting agents without such limitations are urgently needed. By...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-02-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13536 |
| _version_ | 1797320910702641152 |
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| author | Yao‐Yu Hsieh Jia‐Ling Du Pei‐Ming Yang |
| author_facet | Yao‐Yu Hsieh Jia‐Ling Du Pei‐Ming Yang |
| author_sort | Yao‐Yu Hsieh |
| collection | DOAJ |
| description | Microtubule‐targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule‐targeting agents without such limitations are urgently needed. By employing a gene expression‐based drug repositioning strategy, this study identifies VU‐0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules. VU‐0365114 exhibits a broad‐spectrum in vitro anticancer activity, especially in colorectal cancer cells. A tumor xenograft study in nude mice shows that VU‐0365114 slowed the in vivo colorectal tumor growth. The anticancer activity of VU‐0365114 is not related to its original target, M5 mAChR. In addition, VU‐0365114 does not serve as a substrate of multidrug resistance (MDR) proteins, and thus, it can overcome MDR. Furthermore, a kinome analysis shows that VU‐0365114 did not exhibit other significant off‐target effects. Taken together, our study suggests that VU‐0365114 primarily targets microtubules, offering potential for repurposing in cancer treatment, although more studies are needed before further drug development. |
| first_indexed | 2024-03-08T04:49:53Z |
| format | Article |
| id | doaj.art-ac4d479514f04c64864d836760798ff8 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-08T04:49:53Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-ac4d479514f04c64864d836760798ff82024-02-08T06:47:52ZengWileyMolecular Oncology1574-78911878-02612024-02-0118238641410.1002/1878-0261.13536Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistanceYao‐Yu Hsieh0Jia‐Ling Du1Pei‐Ming Yang2Division of Hematology and Oncology Taipei Medical University Shuang Ho Hospital New Taipei City TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology Taipei Medical University New Taipei City TaiwanTaipei Cancer Center Taipei Medical University Taipei TaiwanMicrotubule‐targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule‐targeting agents without such limitations are urgently needed. By employing a gene expression‐based drug repositioning strategy, this study identifies VU‐0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules. VU‐0365114 exhibits a broad‐spectrum in vitro anticancer activity, especially in colorectal cancer cells. A tumor xenograft study in nude mice shows that VU‐0365114 slowed the in vivo colorectal tumor growth. The anticancer activity of VU‐0365114 is not related to its original target, M5 mAChR. In addition, VU‐0365114 does not serve as a substrate of multidrug resistance (MDR) proteins, and thus, it can overcome MDR. Furthermore, a kinome analysis shows that VU‐0365114 did not exhibit other significant off‐target effects. Taken together, our study suggests that VU‐0365114 primarily targets microtubules, offering potential for repurposing in cancer treatment, although more studies are needed before further drug development.https://doi.org/10.1002/1878-0261.13536colorectal cancerconnectivity mapdrug repositioningdrug resistancemicrotubule‐targeting agentpolypharmacology |
| spellingShingle | Yao‐Yu Hsieh Jia‐Ling Du Pei‐Ming Yang Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance Molecular Oncology colorectal cancer connectivity map drug repositioning drug resistance microtubule‐targeting agent polypharmacology |
| title | Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance |
| title_full | Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance |
| title_fullStr | Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance |
| title_full_unstemmed | Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance |
| title_short | Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance |
| title_sort | repositioning vu 0365114 as a novel microtubule destabilizing agent for treating cancer and overcoming drug resistance |
| topic | colorectal cancer connectivity map drug repositioning drug resistance microtubule‐targeting agent polypharmacology |
| url | https://doi.org/10.1002/1878-0261.13536 |
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