What question did this study set out to answer?

The aim is to identify new benzenesulfonanilide-based HDAC inhibitors for treating colon cancer and understand their mechanisms of action.

February 2, 2026

Discovery of Tertiary Benzenesulfonanilide Chemotypes as HDAC Inhibitors via Multistrategy In Silico and Biological Evaluation for Colon Cancer Therapy

Key Result

HIT211504993, a tertiary benzenesulfonanilide HDAC inhibitor, significantly inhibited tumor growth by 77% in an HCT-8 xenograft model compared to SAHA’s 81%.

Key Points

The aim is to identify new benzenesulfonanilide-based HDAC inhibitors for treating colon cancer and understand their mechanisms of action.
Developed a computational pipeline for screening HDAC inhibitors
Evaluated the biological activity of identified compounds in colon cancer cells
Investigated the mechanism of action through various signaling pathways
Identified HIT211504993 as a potent HDAC6 inhibitor with an IC50 of 0.07 μM
HIT211504993 reduced colon cancer cell proliferation and induced apoptosis in vitro
Significantly inhibited tumor growth in an HCT-8 xenograft model (77% inhibition compared to control)

Structured PICO

Does HIT211504993 inhibit tumor growth in colon cancer models?

Population

Colon cancer cells in vitro and HCT-8 xenograft model in vivo

Intervention

HIT211504993 (tertiary benzenesulfonanilide-based HDAC inhibitor) at 20 μM in vitro and 50 mg/kg in vivo

Comparator

SAHA (50 mg/kg) in vivo

Outcome

Tumor growth inhibition and HDAC6 inhibitionsurrogate

HIT211504993 is a novel, potent, and selective HDAC6 inhibitor that demonstrates significant antitumor activity in colon cancer models.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

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.

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