Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction
© 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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021
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| Online Access: | https://hdl.handle.net/1721.1/133551 |
| _version_ | 1826211967464898560 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dash, Radha C |
| collection | MIT |
| description | © 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. |
| first_indexed | 2024-09-23T15:14:14Z |
| format | Article |
| id | mit-1721.1/133551 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:14:14Z |
| publishDate | 2021 |
| publisher | Wiley |
| record_format | dspace |
| spelling | mit-1721.1/1335512021-10-28T03:25:24Z Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction 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 © 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. 2021-10-27T19:53:30Z 2021-10-27T19:53:30Z 2019 2021-08-03T18:29:21Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133551 en 10.1002/CMDC.201900307 ChemMedChem Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley PMC |
| spellingShingle | 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 Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction |
| title | Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction |
| title_full | Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction |
| title_fullStr | Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction |
| title_full_unstemmed | Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction |
| title_short | Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction |
| title_sort | virtual pharmacophore screening identifies small molecule inhibitors of the rev1 ct rir protein protein interaction |
| url | https://hdl.handle.net/1721.1/133551 |
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