Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors

Area of Science:

• Epigenetics
• Medicinal Chemistry
• Oncology

Background:

• Aberrant epigenetic modifications, including histone 3 lysine 9 dimethylation (H3K9Me2) and global histone deacetylation, are linked to diverse cancer phenotypes.
• These epigenetic alterations are recognized as critical therapeutic targets in oncology.
• Specific cancers associated with these epigenetic changes include leukemia, prostate, liver, and lung carcinomas.

Purpose of the Study:

• To identify and develop novel small molecules targeting key epigenetic regulators in cancer.
• To discover the first dual inhibitor effective against both G9a methyltransferase and histone deacetylase (HDAC).

Main Methods:

• Structure-based drug design was employed to guide the development of potential inhibitors.
• Synthesis of small molecules was performed to create candidate compounds.
• Screening assays were utilized to evaluate the inhibitory activity of synthesized compounds against G9a and HDAC.

Main Results:

• Compound 14 was identified as a novel small molecule with dual inhibitory activity.
• Compound 14 demonstrated promising inhibition against both G9a and HDAC enzymes.
• The observed inhibition occurred in the low micromolar range in cell-based assays.

Conclusions:

• The discovery of compound 14 represents a significant advancement in targeting cancer epigenetics.
• This dual inhibitor offers a potential new therapeutic strategy for cancers driven by H3K9Me2 and global deacetylation.
• Further research into compound 14 may lead to novel cancer treatments.