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Publication Detail

Title: Virtual Pharmacophore Screening Identifies Small-Molecule Inhibitors of the Rev1-CT/RIR Protein-Protein Interaction.

Authors: Dash, Radha C; Ozen, Zuleyha; McCarthy, Kaitlyn R; Chatterjee, Nimrat; Harris, Cynthia A; Rizzo, Alessandro A; Walker, Graham C; Korzhnev, Dmitry M; Hadden, M Kyle

Published In ChemMedChem, (2019 09 04)

Abstract: Translesion synthesis (TLS) has emerged as a mechanism through which several forms of cancer develop acquired resistance to first-line genotoxic chemotherapies by allowing replication to continue in the presence of damaged DNA. Small molecules that inhibit TLS hold promise as a novel class of anticancer agents that can serve to enhance the efficacy of these front-line therapies. We previously used a structure-based rational design approach to identify the phenazopyridine scaffold as an inhibitor of TLS that functions by disrupting the protein-protein interaction (PPI) between the C-terminal domain of the TLS DNA polymerase Rev1 (Rev1-CT) and the Rev1 interacting regions (RIR) of other TLS DNA polymerases. To continue the identification of small molecules that disrupt the Rev1-CT/RIR PPI, we generated a pharmacophore model based on the phenazopyridine scaffold and used it in a structure-based virtual screen. In vitro analysis of promising hits identified several new chemotypes with the ability to disrupt this key TLS PPI. In addition, several of these compounds were found to enhance the efficacy of cisplatin in cultured cells, highlighting their anti-TLS potential.

PubMed ID: 31361935 Exiting the NIEHS site

MeSH Terms: Animals; Azo Compounds/pharmacology*; DNA-Directed DNA Polymerase/chemistry; DNA-Directed DNA Polymerase/metabolism*; Drug Evaluation, Preclinical; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Nucleotidyltransferases/chemistry; Nucleotidyltransferases/metabolism*; Protein Binding/drug effects*; Protein Domains; Pyridines/pharmacology*

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