Search

Your search keyword '"Ozen, Zuleyha"' showing total 10 results
Start Over Author "Ozen, Zuleyha"
10 results on '"Ozen, Zuleyha"'

2. Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction

Author

Massachusetts Institute of Technology. Department of Biology, 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, Massachusetts Institute of Technology. Department of Biology, Dash, Radha C., Ozen, Zuleyha, McCarthy, Kaitlyn R., Chatterjee, Nimrat, Harris, Cynthia A., Rizzo, Alessandro A., Walker, Graham C., Korzhnev, Dmitry M., and Hadden, M. Kyle

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.

Published
2022

4. Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction

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

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.

Published
2021

7. Identification of Small Molecule Translesion Synthesis Inhibitors That Target the Rev1-CT/RIR Protein−Protein Interaction

Author

Massachusetts Institute of Technology. Department of Biology, Chatterjee, Nimrat, Walker, Graham C, Sail, Vibhavari, Rizzo, Alessandro A., Dash, Radha C., Ozen, Zuleyha, Korzhnev, Dmitry M., Hadden, M. Kyle, Walker, Graham C., Massachusetts Institute of Technology. Department of Biology, Chatterjee, Nimrat, Walker, Graham C, Sail, Vibhavari, Rizzo, Alessandro A., Dash, Radha C., Ozen, Zuleyha, Korzhnev, Dmitry M., Hadden, M. Kyle, and Walker, Graham C.

Abstract

National Institute of Environmental Health Sciences (Grant R01-ES015818)

Published
2018

9. Epigenetic Silencing of MTAP in Hodgkin's Lymphoma Renders It Sensitive to a 2 ndGeneration PRMT5 Inhibitor

Author

Urosevic, Jelena, Lynch, James T., Meyer, Stefanie, Yusufova, Nevin, Wiseman, Elizabeth, Waring, Paul, Hong, Ted, Ozen, Zuleyha, Wang, Haiyun, Bradshaw, Lauren, Tomczak, Hannah, Chan, Ho Man, Reyes, Ruben, Critchlow, Susan, Younes, Anas, and Dean, Emma

Abstract

Background:PRMT5 is type II arginine methyltransferase that catalyses symmetric dimethylation of arginine residues (SDMA) and plays an important role in cancer biology. By methylating a number of substrates, PRMT5 can regulate important processes such as DNA repair, RNA splicing, and cellular proliferation. In addition, PRMT5 is overexpressed in various cancer types and has been identified as a candidate for therapeutic intervention through the development of small molecules that inhibit PRMT5 methyltransferase activity. However, first generation PRMT5 inhibitors have shown limited clinical benefit mainly due to development of on-target toxicity, primarily in the bone marrow. AstraZeneca has developed a second generation PRMT5 inhibitor (AZ-PRMT5i), that selectively inhibits PRMT5 in MTAP deficient tumours while sparing MTAP proficient normal cells. MTAP (methylthioadenosine phosphorylase) is a metabolic enzyme involved in methionine salvage pathway. MTAP deficiency results in accumulation of the metabolite methylothioadenosine (MTA) in tumor cells that induces partial inhibition of PRMT5, rendering these tumors sensitive to PRMT5 inhibition. Homozygous deletion of the MTAPgene, that results in the loss of MTAP protein, has been found in approximately 15% of advanced solid tumors. Here, for the first time, we describe epigenetic silencing of the MTAPgene in Hodgkin's Lymphoma (HL) cell lines. This silencing results in the loss of MTAP protein expression thus increasing sensitivity to PRMT5 inhibition. Importantly, MTAP protein loss was also observed in primary cHL samples, opening a novel opportunity for the treatment of HL.

Published
2023
Full Text
View/download PDF

10. Identification of Small Molecule Translesion Synthesis Inhibitors That Target the Rev1-CT/RIR Protein-Protein Interaction.

Author

Sail V, Rizzo AA, Chatterjee N, Dash RC, Ozen Z, Walker GC, Korzhnev DM, and Hadden MK

Subjects
Animals, Binding Sites, Cell Line, Tumor, Cells, Cultured, DNA-Binding Proteins metabolism, Drug Discovery, Enzyme Activation drug effects, Humans, Inhibitory Concentration 50, Mice, Models, Molecular, Molecular Dynamics Simulation, Nuclear Proteins genetics, Nucleic Acid Synthesis Inhibitors chemistry, Nucleotidyltransferases genetics, Proteins chemistry, Small Molecule Libraries chemistry, DNA-Directed DNA Polymerase metabolism, Drug Delivery Systems, Nuclear Proteins metabolism, Nucleic Acid Synthesis Inhibitors pharmacology, Nucleotidyltransferases metabolism, Small Molecule Libraries pharmacology
Abstract

Translesion synthesis (TLS) is an important mechanism through which proliferating cells tolerate DNA damage during replication. The mutagenic Rev1/Polζ-dependent branch of TLS helps cancer cells survive first-line genotoxic chemotherapy and introduces mutations that can contribute to the acquired resistance so often observed with standard anticancer regimens. As such, inhibition of Rev1/Polζ-dependent TLS has recently emerged as a strategy to enhance the efficacy of first-line chemotherapy and reduce the acquisition of chemoresistance by decreasing tumor mutation rate. The TLS DNA polymerase Rev1 serves as an integral scaffolding protein that mediates the assembly of the active multiprotein TLS complexes. Protein-protein interactions (PPIs) between the C-terminal domain of Rev1 (Rev1-CT) and the Rev1-interacting region (RIR) of other TLS DNA polymerases play an essential role in regulating TLS activity. To probe whether disrupting the Rev1-CT/RIR PPI is a valid approach for developing a new class of targeted anticancer agents, we designed a fluorescence polarization-based assay that was utilized in a pilot screen for small molecule inhibitors of this PPI. Two small molecule scaffolds that disrupt this interaction were identified, and secondary validation assays confirmed that compound 5 binds to Rev1-CT at the RIR interface. Finally, survival and mutagenesis assays in mouse embryonic fibroblasts and human fibrosarcoma HT1080 cells treated with cisplatin and ultraviolet light indicate that these compounds inhibit mutagenic Rev1/Polζ-dependent TLS in cells, validating the Rev1-CT/RIR PPI for future anticancer drug discovery and identifying the first small molecule inhibitors of TLS that target Rev1-CT.

Published
2017
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results