A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Dysregulated polycomb protein activity drives oncogenesis via aberrant gene silencing.
• Enhancer of Zeste Homolog 2 (EZH2) is a key therapeutic target in cancer, with approved inhibitors showing clinical efficacy.
• Existing EZH2 inhibitors exhibit poor brain penetration, limiting their application in central nervous system (CNS) malignancies.

Purpose of the Study:

• To develop novel EZH2 inhibitors with improved brain penetrance for CNS cancer treatment.
• To identify chemical strategies for minimizing P-glycoprotein activity in EZH2 inhibitor scaffolds.
• To discover potent and peripherally active EZH2 inhibitors for broader oncological applications.

Main Methods:

• Computational modeling of pyridone-containing EZH2 inhibitor scaffolds.
• Chemical synthesis and optimization of EZH2 inhibitor compounds.
• Evaluation of brain penetrance and P-glycoprotein activity of novel inhibitors.

Main Results:

• Identification of TDI-6118 (compound 5), the first brain-penetrant EZH2 inhibitor.
• TDI-6118 demonstrated minimized P-glycoprotein activity through a pyridone-based chemical strategy.
• Discovery of TDI-11904 (compound 21), a potent, peripherally active EZH2 inhibitor with a novel 7-member ring structure.

Conclusions:

• TDI-6118 represents a significant advancement for treating CNS malignancies sensitive to EZH2 inhibition.
• The developed chemical strategy enables the design of brain-penetrant EZH2 inhibitors.
• TDI-11904 offers a new therapeutic option for peripheral EZH2-driven cancers.