Virtual Pharmacophore Screening Identifies Small- Molecule Inhibitors of pe Rev1-CT/RIR Protein–Protein Interaction

摘要

Translesionsynpesis (TLS) has emerged as amechanism prough which several forms of cancer developacquired resist- ance to first-line genotoxic chemoperapies by allowing repli- cation to continue in pe presence of damaged DNA. Small molecules pat inhibitTLS hold promise as anovel class of an- ticanceragents pat can serve to enhancepe efficacy of pese front-line perapies. We previously used astructure-based ra- tional design approach to identify pe phenazopyridine scaf- fold as an inhibitor of TLS pat functions by disrupting pe pro- tein–protein interaction (PPI) between pe C-terminal domain of pe TLS DNA polymerase Rev1 (Rev1-CT) and pe Rev1 inter- acting regions (RIR) of oper TLS DNA polymerases. To continue pe identification of small molecules pat disrupt pe Rev1-CT/ RIR PPI, we generated apharmacophore model based on pe phenazopyridine scaffold and used it in astructure-based virtu- al screen. In vitro analysis of promising hits identified several new chemotypeswip pe ability to disrupt pis key TLS PPI. In addition, several of pese compounds were found to enhance pe efficacy of cisplatin in cultured cells, highlightingpeir anti- TLS potential.