Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor...

Area of Science:

• Oncology
• Epigenetics
• Pharmacology

Background:

• Epigenetic modifications play a crucial role in cancer development.
• Current epigenetic therapies often involve targeting DNA methyltransferases (DNMTs) or histone deacetylases (HDACs) individually.
• Developing dual inhibitors offers a potential strategy to enhance therapeutic efficacy by targeting multiple epigenetic pathways simultaneously.

Purpose of the Study:

• To design and synthesize novel dual inhibitors of DNMT1 and HDAC by combining key pharmacophores.
• To evaluate the in vitro and in vivo efficacy of these dual inhibitors in preclinical cancer models.
• To assess the potential of these compounds in reversing cancer-specific epigenetic alterations and their impact on the tumor microenvironment.

Main Methods:

• Fusion of DNMT1 inhibitor and HDAC inhibitor pharmacophores to create dual-acting compounds.
• In vitro and cellular assays to assess DNMT1 and HDAC inhibition.
• In vivo studies using MV-4-11 xenograft and MC38 syngeneic mouse models.
• Analysis of tumor growth inhibition, tolerability, and tumor immune microenvironment modulation.

Main Results:

• Compound (±)-23a demonstrated potent DNMT1 and HDAC inhibition.
• It effectively reactivated epigenetically silenced tumor suppressor genes (TSGs).
• In vivo, (±)-23a achieved 98% tumor growth inhibition in the MV-4-11 model with improved tolerability and outperformed combination therapy in the MC38 model by inducing tumor regression and reshaping the tumor immune microenvironment.

Conclusions:

• The novel DNMT1/HDAC dual inhibitor (±)-23a shows significant promise as a cancer therapeutic agent.
• It effectively reverses cancer-specific epigenetic abnormalities.
• (±)-23a holds potential for further clinical development in oncology.