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

The SWI/SNF chromatin remodeling complex regulates numerous cellular processes, and inactivating mutations in its subunit, SMARCA4, are closely associated with various malignancies. The inactivation of SMARCA4 has been found to have a synthetic lethal relationship with the inhibition of SMARCA2 ATPase, suggesting that targeted inhibition of SMARCA2 ATPase in SMARCA4-deficient environments presents a promising tumor treatment option. In this study, we identified binding pockets with selective modification potential through mixed-solvent molecular dynamics simulations. Additionally, several selective inhibitors of SMARCA2 ATPase were identified by virtual screening, and preliminary structural modifications were conducted. Among them, compounds 4 and 11 demonstrated inhibitory activity at micromolar level and exhibited selectivity. Overall, these findings validate the efficacy of our virtual screening approach and provide a promising novel scaffold for the development of highly selective SMARCA2 ATPase inhibitors.

SMARCA2; SMARCA4; molecular dynamics; selective inhibitors; virtual screening.