Discovery of Novel Selective Inhibitors of SMARCA2 ATPase Domain by Virtual Screening and Biological Evaluation

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• The SWI/SNF chromatin remodeling complex is crucial for cellular processes.
• Inactivating mutations in SMARCA4 are linked to various cancers.
• SMARCA4 inactivation exhibits synthetic lethality with SMARCA2 ATPase inhibition.

Purpose of the Study:

• To identify selective SMARCA2 ATPase inhibitors for SMARCA4-deficient cancers.
• To explore potential binding pockets for targeted drug development.

Main Methods:

• Mixed-solvent molecular dynamics simulations to identify binding pockets.
• Virtual screening to discover selective SMARCA2 ATPase inhibitors.
• Preliminary structural modifications of identified compounds.

Main Results:

• Selective binding pockets with modification potential were identified.
• Several selective SMARCA2 ATPase inhibitors were discovered via virtual screening.
• Compounds 4 and 11 demonstrated micromolar inhibitory activity and selectivity.

Conclusions:

• The virtual screening approach is effective for identifying SMARCA2 ATPase inhibitors.
• Compounds 4 and 11 represent promising scaffolds for developing selective SMARCA2 inhibitors.
• Targeting SMARCA2 ATPase is a viable therapeutic strategy for SMARCA4-mutant cancers.