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Updated: Feb 25, 2026
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
In silico discovery and biological evaluation of a novel selective HDAC8 inhibitor featuring
Wenying Yan1, He Shi2, Tingting Li3
1Department of Clinical Pharmacy, Hebei Medical University Third Hospital, Shijiazhuang 050051, China.
Abstract:
Histone deacetylase 8 (HDAC8), a pivotal epigenetic regulator orchestrating chromatin remodeling and transcriptional control, has emerged as a compelling anticancer target owing to its frequent dysregulation in malignancies. The development of isoform-selective inhibitors, however, confronts substantial challenges because of the pronounced structural conservation across HDAC isoforms. This study developed a high-efficiency drug screening pipeline primarily leveraging artificial learning (AI) models and molecular simulation techniques, and further evaluated the biological activity of computationally prioritized compounds through enzymatic inhibition assays and cellular experiments. The structurally novel compound Cmpd.16 was successfully identified, exhibiting promising inhibitory activity against HDAC8 (IC50 = 0.16 ± 0.01 μM) and moderately inhibited HCT116 cell proliferation mainly through the induction of apoptosis and G2/M phase cell cycle arrest. Subsequently, molecular dynamics simulations were employed to investigate the binding conformation of Cmpd.16 within the active pocket, and the key residues identified through free energy decomposition further elucidated the drug-target binding mode. Collectively, Cmpd.16, featuring 1H-pyrazolo[3,4-b]pyridine scaffold, was discovered via an efficient screening workflow, offering valuable insights to guide the rational design of HDAC8-targeted agents.
Insights
A novel compound, Cmpd.16, was identified using AI and simulations to target Histone deacetylase 8 (HDAC8). This HDAC8 inhibitor shows anticancer potential by halting cell proliferation and inducing apoptosis.
Area of Science:
- Epigenetics and Molecular Biology
- Medicinal Chemistry
- Computational Drug Discovery
Background:
- Histone deacetylase 8 (HDAC8) is a key epigenetic regulator frequently dysregulated in cancers, making it a significant anticancer target.
- Developing isoform-selective HDAC inhibitors is challenging due to structural similarities among HDAC family members.
Purpose of the Study:
- To establish an efficient drug screening pipeline utilizing artificial intelligence (AI) and molecular simulations.
- To identify and characterize novel, selective inhibitors of HDAC8 for potential cancer therapy.
Main Methods:
- High-throughput drug screening pipeline integrating AI models and molecular simulations.
- Enzymatic inhibition assays and cellular experiments to evaluate compound activity.
- Molecular dynamics simulations and free energy decomposition to analyze drug-target interactions.
Main Results:
- Identification of a novel compound, Cmpd.16, with potent HDAC8 inhibitory activity (IC50 = 0.16 ± 0.01 μM).
- Cmpd.16 demonstrated moderate inhibition of HCT116 cell proliferation via apoptosis induction and G2/M cell cycle arrest.
- Molecular simulations elucidated the binding mode of Cmpd.16 within the HDAC8 active site.
Conclusions:
- Cmpd.16, based on a 1H-pyrazolo[3,4-b]pyridine scaffold, was discovered through an efficient AI-driven screening process.
- The findings provide valuable insights for the rational design of targeted HDAC8 inhibitors in cancer treatment.
