Design, Synthesis, and Biological Evaluation of Potent EZH2/LSD1 Dual Inhibitors for Prostate Cancer

Area of Science:

• Epigenetics
• Medicinal Chemistry
• Oncology

Background:

• Enhancer of Zeste Homolog 2 (EZH2) and Lysine Specific Demethylase 1 (LSD1) are histone modification enzymes implicated in cancer.
• Combined inhibition of EZH2 and LSD1 has shown synergistic anticancer effects in leukemia and prostate cancer.

Purpose of the Study:

• To design and synthesize novel dual inhibitors targeting both EZH2 and LSD1.
• To evaluate the anticancer activity of these dual inhibitors, particularly against prostate cancer cell lines.

Main Methods:

• Structure-activity relationship (SAR) studies were conducted to optimize inhibitor design.
• In vitro enzymatic assays and Western blot analyses were used to confirm target engagement and molecular effects.
• In vivo studies using a 22RV1 xenograft mouse model were performed to assess therapeutic efficacy.

Main Results:

• Compound ML234 demonstrated potent antiproliferative activity against LNCAP, PC3, and 22RV1 prostate cancer cell lines.
• ML234 was confirmed to act as a dual inhibitor of EZH2 and LSD1, leading to specific changes in histone methylation marks (H3K4me2, H3K9me2, H3K27me3).
• In vivo, ML234 significantly suppressed tumor growth and enhanced the efficacy of enzalutamide in a prostate cancer mouse model.

Conclusions:

• ML234 is a promising EZH2/LSD1 dual inhibitor with significant anticancer potential for prostate cancer.
• The compound's ability to modulate key epigenetic marks and suppress tumor growth warrants further investigation as a therapeutic agent.