Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance

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Title:	Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance
Authors:	楊培銘 Hsieh, Y. Y., Du, J. L., & Yang, P. M.
Contributors:	癌症生物學與藥物研發研究所
Keywords:	colorectal cancer;connectivity map;drug repositioning;drug resistance;microtubule-targeting agent;polypharmacology.
Date:	2024-02
Issue Date:	2024-12-04 14:05:38 (UTC+8)
Abstract:	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.
Relation:	Molecular oncology, 18(2), 386–414
Description:	【112-2 升等】臺北醫學大學教師升等專門著作職別：專任送審等級：教授著作送審
Note:	代表著作名稱：《Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance》 ? 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Data Type:	article
Appears in Collections:	[Scholarly output for promotion] 112 [Master Program in Graduate Institute of Cancer Biology and Drug Discovery] article

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