SAH derived potent and selective EZH2 inhibitors

Area of Science:

• Medicinal Chemistry
• Epigenetics
• Biochemistry

Background:

• Enhancer of zeste homolog 2 (EZH2) is a key histone methyltransferase (HMT) in epigenetic regulation.
• Dysregulation of EZH2 is implicated in various diseases, including cancer.
• S-adenosyl-l-homocysteine (SAH) is a natural inhibitor of HMTs, serving as a structural template.

Purpose of the Study:

• To design and synthesize novel nucleoside-based inhibitors targeting EZH2.
• To evaluate the inhibitory activity of these compounds against wild-type (WT) and mutant (Y641N) PRC2 complexes.
• To characterize the potency, lipophilic efficiency (LipE), and selectivity of the lead compound.

Main Methods:

• Structure-based drug design utilizing the SAH scaffold.
• Synthesis of novel nucleoside analogs.
• Biochemical assays to measure inhibition of H3K27 methylation by PRC2 complexes.
• Determination of IC50 values and assessment of selectivity against other lysine methyltransferases.

Main Results:

• A series of novel EZH2 inhibitors were successfully designed and synthesized.
• The inhibitors effectively blocked H3K27 methylation in biochemical assays.
• Compound 27 demonstrated significant potency, with IC50 values of 270 nM and 70 nM against WT and Y641N PRC2, respectively.
• Compound 27 exhibited improved potency, LipE, and selectivity compared to SAH.

Conclusions:

• Compound 27 represents a highly potent SAH-derived inhibitor of the EZH2 PRC2 complex.
• This novel inhibitor shows promise for further development in epigenetic therapies.
• The findings provide a valuable foundation for the design of next-generation EZH2 inhibitors.