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

Author:

Hsieh Yao‐Yu1234,Du Jia‐Ling5,Yang Pei‐Ming34567ORCID

Affiliation:

1. Division of Hematology and Oncology Taipei Medical University Shuang Ho Hospital New Taipei City Taiwan

2. Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine Taipei Medical University Taipei Taiwan

3. Taipei Cancer Center Taipei Medical University Taipei Taiwan

4. TMU and Affiliated Hospitals Pancreatic Cancer Groups Taipei Medical University Taipei Taiwan

5. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology Taipei Medical University New Taipei City Taiwan

6. Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology Taipei Medical University New Taipei City Taiwan

7. TMU Research Center of Cancer Translational Medicine Taipei Taiwan

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.

Funder

Taipei Medical University

Publisher

Wiley

Subject

Cancer Research,Genetics,Molecular Medicine,General Medicine,Oncology

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