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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer
Maria Chiara Pismataro1, Andrea Astolfi1, Maria Letizia Barreca1
1Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy.
Abstract:
Synthetic lethality (SL) is an innovative strategy in targeted anticancer therapy that exploits tumor genetic vulnerabilities. This topic has come to the forefront in recent years, as witnessed by the increased number of publications since 2007. The first proof of concept for the effectiveness of SL was provided by the approval of poly(ADP-ribose)polymerase inhibitors, which exploit a SL interaction in BRCA-deficient cells, although their use is limited by resistance. Searching for additional SL interactions involving BRCA mutations, the DNA polymerase theta (POLθ) emerged as an exciting target. This review summarizes, for the first time, the POLθ polymerase and helicase inhibitors reported to date. Compounds are described focusing on chemical structure and biological activity. With the aim to enable further drug discovery efforts in interrogating POLθ as a target, we propose a plausible pharmacophore model for POLθ-pol inhibitors and provide a structural analysis of the known POLθ ligand binding sites.
Insights
Synthetic lethality exploits tumor vulnerabilities for cancer therapy. DNA polymerase theta (POLθ) is a promising target for BRCA-mutated cancers, with new inhibitors and models emerging.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Synthetic lethality (SL) offers targeted cancer therapy by exploiting genetic vulnerabilities.
- Poly(ADP-ribose)polymerase (PARP) inhibitors demonstrate SL in BRCA-deficient cells but face resistance.
- DNA polymerase theta (POLθ) presents a novel SL target for BRCA-mutated cancers.
Purpose of the Study:
- To review existing POLθ polymerase and helicase inhibitors.
- To enable further drug discovery by proposing a pharmacophore model for POLθ-pol inhibitors.
- To provide structural insights into POLθ ligand binding sites.
Main Methods:
- Literature review of POLθ inhibitors.
- Chemical structure and biological activity analysis.
- Pharmacophore modeling and structural analysis of ligand binding sites.
Main Results:
- Summary of reported POLθ polymerase and helicase inhibitors.
- Proposal of a pharmacophore model for POLθ-pol inhibitors.
- Structural analysis of POLθ ligand binding sites.
Conclusions:
- POLθ is a promising target for synthetic lethality-based cancer therapy.
- Understanding POLθ inhibitors and binding sites can guide future drug development.
- Further research into POLθ inhibitors may overcome resistance seen with current therapies.
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