Functional Characterization of VS-186B, a Novel HDAC Inhibitor with Anticancer Activity

Sanchez-Michael, Laura A.; Sudarshan, Vijayalakshmi; Elias, Allison; Gutierrez, Denisse A.; Lopez-Saenz, Jose A.; Pena-Zacarias, Jaqueline; Torres, Gabriela C.; Varela-Ramirez, Armando; Kumar, Sujeet; Karki, Subhas S.; Aguilera, Renato J.

doi:10.3390/ijms262311354

This is an early access version, the complete PDF, HTML, and XML versions will be available soon.

Open AccessArticle

Functional Characterization of VS-186B, a Novel HDAC Inhibitor with Anticancer Activity

by

Laura A. Sanchez-Michael

^1,†

,

Vijayalakshmi Sudarshan

^2,3,4,†

,

Allison Elias

¹

,

Denisse A. Gutierrez

¹

,

Jose A. Lopez-Saenz

¹,

Jaqueline Pena-Zacarias

¹

,

Gabriela C. Torres

¹

,

Armando Varela-Ramirez

¹

,

Sujeet Kumar

⁵

,

Subhas S. Karki

^2,3,*

and

Renato J. Aguilera

^1,*

¹

Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA

²

Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Bengaluru 560010, Karnataka, India

³

KLE Academy of Higher Education and Research, KLE Deemed to be University, Belagavi 590010, Karnataka, India

⁴

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru 560054, Karnataka, India

⁵

Department of Pharmaceutical Chemistry, NITTE College of Pharmaceutical Sciences, Nitte-Deemed to be University, Mangaluru, Yelahanka, Bengaluru 560064, Karnataka, India

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(23), 11354; https://doi.org/10.3390/ijms262311354

Submission received: 25 September 2025 / Revised: 10 November 2025 / Accepted: 16 November 2025 / Published: 24 November 2025

(This article belongs to the Special Issue Novel Molecular Mechanisms Underlying Tumorigenesis and Innovative Therapeutic Approaches for Cancer-Fighting, 3rd Edition)

Download

Browse Figure

Versions Notes

Abstract

Histone acetylation and deacetylation are key regulators of gene expression and are frequently dysregulated in cancer, contributing to tumorigenesis and drug resistance. Overexpression of histone deacetylases (HDACs) in many cancer types leads to silencing of tumor suppressor genes and uncontrolled proliferation. Tumors often rely on epigenetic mechanisms to escape therapy and develop resistance. This study aimed to identify novel compounds that selectively target cancer cells while minimizing toxicity to non-cancerous cell lines. A series of novel HDAC inhibitors was evaluated using the Differential Nuclear Staining (DNS) assay, flow cytometry, and HDAC inhibition assays. These assays assessed cytotoxicity, selectivity, and mechanisms of cell death. Among seven compounds tested, VS-186B exhibited the highest cytotoxicity and Selective Cytotoxicity Index (SCI), particularly against the human Jurkat T-cell leukemia cell line. Flow cytometry experiments (Annexin V-FITC, ROS, JC-1, and Caspase-3/7 assays) revealed that VS-186B induced apoptosis. VS-186B was more cytotoxic than Curcumin and Vorinostat across most of the cell lines tested and was more specific to hematological cells. Connectivity Map (CMap) analysis showed strong similarity to genes affected by known HDAC inhibitors. Subsequently, HDAC enzymatic assays confirmed that VS-186B inhibits Class I and II HDACs in a dose-dependent manner. VS-186B exhibits promising anticancer potential as a selective HDAC inhibitor since it induces apoptosis in cancer cells without significant cytotoxicity to non-cancerous lines with a similar gene expression profile to known HDAC inhibitors. These findings support further development of VS-186B as an epigenetic treatment for leukemia/lymphoma.

Keywords: cytotoxicity; apoptosis; HDAC inhibitor; anti-cancer; selectivity; curcumin; Vorinostat; leukemia; Jurkat

Graphical Abstract

Share and Cite

MDPI and ACS Style

Sanchez-Michael, L.A.; Sudarshan, V.; Elias, A.; Gutierrez, D.A.; Lopez-Saenz, J.A.; Pena-Zacarias, J.; Torres, G.C.; Varela-Ramirez, A.; Kumar, S.; Karki, S.S.; et al. Functional Characterization of VS-186B, a Novel HDAC Inhibitor with Anticancer Activity. Int. J. Mol. Sci. 2025, 26, 11354. https://doi.org/10.3390/ijms262311354

AMA Style

Sanchez-Michael LA, Sudarshan V, Elias A, Gutierrez DA, Lopez-Saenz JA, Pena-Zacarias J, Torres GC, Varela-Ramirez A, Kumar S, Karki SS, et al. Functional Characterization of VS-186B, a Novel HDAC Inhibitor with Anticancer Activity. International Journal of Molecular Sciences. 2025; 26(23):11354. https://doi.org/10.3390/ijms262311354

Chicago/Turabian Style

Sanchez-Michael, Laura A., Vijayalakshmi Sudarshan, Allison Elias, Denisse A. Gutierrez, Jose A. Lopez-Saenz, Jaqueline Pena-Zacarias, Gabriela C. Torres, Armando Varela-Ramirez, Sujeet Kumar, Subhas S. Karki, and et al. 2025. "Functional Characterization of VS-186B, a Novel HDAC Inhibitor with Anticancer Activity" International Journal of Molecular Sciences 26, no. 23: 11354. https://doi.org/10.3390/ijms262311354

APA Style

Sanchez-Michael, L. A., Sudarshan, V., Elias, A., Gutierrez, D. A., Lopez-Saenz, J. A., Pena-Zacarias, J., Torres, G. C., Varela-Ramirez, A., Kumar, S., Karki, S. S., & Aguilera, R. J. (2025). Functional Characterization of VS-186B, a Novel HDAC Inhibitor with Anticancer Activity. International Journal of Molecular Sciences, 26(23), 11354. https://doi.org/10.3390/ijms262311354

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Functional Characterization of VS-186B, a Novel HDAC Inhibitor with Anticancer Activity

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI