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Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
Published on: November 11, 2016
Virtual Pharmacophore Screening Identifies Small-Molecule Inhibitors of the Rev1-CT/RIR Protein-Protein Interaction
Radha C Dash1, Zuleyha Ozen1, Kaitlyn R McCarthy1
1Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06269, USA.
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.
Insights
New small molecules targeting translesion synthesis (TLS) DNA repair were identified. These compounds disrupt a key protein interaction, showing potential to overcome cancer
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Translesion synthesis (TLS) enables cancer cells to resist genotoxic chemotherapy by replicating damaged DNA.
- Inhibiting TLS is a promising strategy to enhance chemotherapy efficacy.
- Phenazopyridine scaffolds were previously identified as inhibitors of the Rev1-CT/RIR protein-protein interaction (PPI) crucial for TLS.
Purpose of the Study:
- To identify novel small molecules that disrupt the Rev1 C-terminal domain (Rev1-CT) and Rev1 interacting regions (RIR) PPI.
- To discover new chemotypes with anti-TLS activity.
- To evaluate the potential of identified compounds to enhance chemotherapy efficacy.
Main Methods:
- Structure-based virtual screening using a pharmacophore model derived from phenazopyridine scaffolds.
- In vitro analysis of identified compounds for their ability to disrupt the Rev1-CT/RIR PPI.
- Assessment of compound efficacy in enhancing cisplatin treatment in cell cultures.
Main Results:
- A pharmacophore model successfully guided virtual screening.
- Several new chemotypes capable of disrupting the Rev1-CT/RIR PPI were identified.
- Some identified compounds demonstrated the ability to enhance cisplatin's efficacy in cellular models.
Conclusions:
- Novel small molecules targeting the Rev1-CT/RIR PPI were discovered.
- These compounds represent a new class of potential anti-TLS agents.
- The findings support the development of TLS inhibitors to improve cancer treatment outcomes.
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