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Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction
Name
nihms-1045877.pdf
Description
Accepted version
Size
1.15 MB
Format
Adobe PDF
Checksum (MD5)
8156386361b758fb2614403b8b7d3487
Author(s)
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
Date Issued
2019
Journal
ChemMedChem
Publisher
Wiley
Version
Author's final manuscript
Abstract
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 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.
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
10.1002/CMDC.201900307
