Pan-histone demethylase inhibitors simultaneously targeting Jumonji C and lysine-specific demethylases display high...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Epigenetics

Background:

• Histone lysine demethylases (KDMs), specifically LSD1/KDM1 and JMJD2/KDM4, are coexpressed with androgen receptors in prostate cancer.
• Simultaneous targeting of these KDMs presents a potential therapeutic strategy.

Purpose of the Study:

• To design and synthesize novel hybrid inhibitors targeting both LSD1/KDM1 and JMJD2/KDM4 families.
• To evaluate the efficacy and cancer-selectivity of these pan-KDM inhibitors.

Main Methods:

• Hybrid inhibitors (compounds 1-6) were synthesized by coupling tranylcypromine (LSD1 inhibitor) with 2-oxoglutarate competitive templates for JmjC inhibition.
• In vitro studies assessed the impact of compounds on histone methylation levels (H3K4, H3K9) and their effects on cancer cell lines (LNCaP, HCT116) and non-cancer cells (MePR).

Main Results:

• Hybrid compounds 1-6 were synthesized and validated as potential antitumor agents.
• Compounds 2 and 3 significantly increased H3K4 and H3K9 methylation.
• Compounds 2 and 3 induced cell growth arrest and apoptosis in LNCaP and HCT116 cells, with minimal impact on MePR cells, indicating cancer-selective action.

Conclusions:

• Novel hybrid pan-KDM inhibitors (compounds 2 and 3) demonstrate potent anticancer activity.
• These compounds exhibit cancer-selective apoptosis induction, highlighting their therapeutic potential for prostate and colon cancers.
• The findings support the simultaneous targeting of LSD1/KDM1 and JMJD2/KDM4 as a viable anticancer strategy.