HIT211504993

Histone deacetylase (HDAC) inhibitors exert anticancer effects through epigenetic regulation. Developing HDAC inhibitors with different chemical types represents a promising anticancer treatment strategy. Herein, we established an enhanced comprehensive computational pipeline to identify tertiary benzenesulfonanilide-based HDAC inhibitor lead compounds and elucidate activity differences among derivatives based on electronic properties. Highly active HIT211504993 is a potent inhibitor selective for HDAC6 (IC₅₀ = 0.07 μM) over HDAC2 and HDAC4. HIT211504993 (20 μM) suppresses colon cancer cell proliferation and induces apoptosis in vitro and significantly inhibits tumor growth (50 mg/kg, 77%) in an HCT-8 xenograft model, comparable to SAHA (50 mg/kg, 81%). Mechanistically, HIT211504993 inhibits Myc-driven tumorigenesis by promoting nucleocytoplasmic acetylation and modulating p53, cell-cycle, and Wnt/β-catenin signaling. The investigation of antitumor activity and its mechanism of action provides a theoretical basis for the development of the next-generation benzenesulfonanilide HDAC inhibitors.