Abstract C030: Functional characterization of VS-186B, a novel HDAC inhibitor for cancer treatment

Abstract Cancer progression and therapeutic resistance are often driven by epigenetic dysregulation, including disruptions in the balance of histone acetylation and deacetylation. Histone deacetylases (HDACs) are frequently overexpressed in various cancers, contributing to the silencing of tumor suppressor genes and uncontrolled cell proliferation. This study evaluated a panel of novel HDAC inhibitors to identify candidates with selective cytotoxicity toward cancer cells while minimizing toxicity to non-cancerous cells. Compounds were assessed using the Differential Nuclear Staining (DNS) assay, flow cytometry, RNA sequencing, and HDAC enzymatic assays to characterize cytotoxicity and mechanisms of cell death. Of the seven HDAC inhibitors tested, VS-186B demonstrated the greatest potency and highest Selective Cytotoxic Index (SCI), particularly in Jurkat T-cell leukemia cells. Flow cytometry analyses using Annexin V-FITC, ROS, JC-1, and Caspase-3/7 confirmed activation of the intrinsic apoptotic pathway. VS-186B exhibited greater cytotoxic activity than both Curcumin and the FDA-approved HDAC inhibitor SAHA (Vorinostat) across a range of hematological and solid tumor cell lines, with enhanced specificity toward hematological cells. Transcriptomic analysis revealed significant changes in gene expression following VS-186B treatment, and Connectivity Map (CMap) analysis indicated a strong similarity to the transcriptional profiles of known HDAC inhibitors. HDAC enzymatic assays confirmed dose-dependent inhibition of Class I and II HDACs. These findings highlight VS-186B as a promising epigenetic therapeutic candidate for the treatment of leukemia and lymphoma. Citation Format: Allison Elias, Denisse A. Gutierrez, Jose A. Lopez-Saenz, Jaqueline Pena-Zacarias, Gabriela C. Torres, Armando Varela-Ramirez, Vijayalakshmi S, Subhas S. Karki, Renato Aguilera, Laura A. Sanchez-Michael. Functional characterization of VS-186B, a novel HDAC inhibitor for cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C030.