Discovery of RP-37 Analogues as Potent, Selective Irreversible Inhibitors Targeting DNA Polymerase Theta (POLθ)

Key Points

• The research aims to discover potent and selective irreversible inhibitors of DNA polymerase theta for treating BRCA-deficient cancers.
• Structure-guided drug design was utilized to develop RP-37 analogues.
• The efficacy of the inhibitors was tested in cellular assays to evaluate their potencies against POLθ.
• Selectivity was assessed to compare the analogs versus reversible inhibitors.
• RP-37 analogues demonstrated significantly higher potency compared to existing reversible POLθ inhibitors.
• These analogues showed selective inhibition of DNA polymerase theta, disrupting its function in BRCA-deficient cancer cells.
• Improved cellular efficacy was observed, suggesting better theoretical treatment outcomes in target populations.