2. Academic Validation
  3. Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance

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

  • Mol Oncol. 2024 Feb;18(2):386-414. doi: 10.1002/1878-0261.13536.
Yao-Yu Hsieh 1 2 3 4,  Jia-Ling Du 5,  Pei-Ming Yang 3 4 5 6 7 8
Affiliations

Affiliations

  • 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.
  • 8 Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
PMID: 37842807 DOI: 10.1002/1878-0261.13536
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.

Keywords

colorectal cancer; connectivity map; drug repositioning; drug resistance; microtubule-targeting agent; polypharmacology.

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