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Lead compound profiling for small molecule inhibitors of the REV1-CT/RIR Translesion synthesis Protein-Protein
Angela M Zaino1, Radha Charan Dash1, Stephy J James1
1Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA.
Abstract:
Translesion synthesis (TLS) is a cellular mechanism through which actively replicating cells recruit specialized, low-fidelity DNA polymerases to damaged DNA to allow for replication past these lesions. REV1 is one of these TLS DNA polymerases that functions primarily as a scaffolding protein to organize the TLS heteroprotein complex and ensure replication occurs in the presence of DNA lesions. The C-Terminal domain of REV1 (REV1-CT) forms many protein-protein interactions (PPIs) with other TLS polymerases, making it essential for TLS function and a promising drug target for anti-cancer drug development. We utilized several lead identification strategies to identify various small molecules capable of disrupting the PPI between REV1-CT and the REV1 Interacting Regions (RIR) present in several other TLS polymerases. These lead compounds were profiled in several in vitro potency and PK assays to identify two scaffolds (1 and 6) as the most promising for further development. Both 1 and 6 synergized with cisplatin in a REV1-dependent fashion and demonstrated promising in vivo PK and toxicity profiles.
Insights
Researchers identified small molecules that disrupt protein interactions in translesion synthesis (TLS), a DNA repair process. These compounds show promise for anti-cancer drug development by enhancing chemotherapy effectiveness.
Area of Science:
- Molecular Biology
- Drug Discovery
- Cancer Research
Background:
- Translesion synthesis (TLS) is crucial for DNA repair, utilizing specialized polymerases to bypass DNA lesions during replication.
- REV1 acts as a scaffold protein in TLS, organizing the complex and facilitating lesion bypass.
- The REV1 C-Terminal domain (REV1-CT) is vital for TLS and a potential anti-cancer drug target due to its protein-protein interactions (PPIs).
Purpose of the Study:
- To identify small molecules that disrupt the PPI between REV1-CT and REV1 Interacting Regions (RIRs) of other TLS polymerases.
- To evaluate the therapeutic potential of these small molecules as anti-cancer agents.
Main Methods:
- Lead identification strategies were employed to find small molecules targeting the REV1-CT/RIR interaction.
- In vitro potency and pharmacokinetic (PK) assays were used to profile lead compounds.
- Synergy with cisplatin and in vivo PK/toxicity profiles were assessed for promising scaffolds.
Main Results:
- Several small molecules were identified that disrupt the REV1-CT and RIR PPI.
- Two scaffolds (1 and 6) demonstrated significant promise in potency and PK assays.
- Compounds 1 and 6 showed REV1-dependent synergy with cisplatin and favorable in vivo PK and toxicity profiles.
Conclusions:
- Small molecules targeting the REV1-CT/RIR interaction can be developed as potential anti-cancer therapeutics.
- Scaffolds 1 and 6 represent promising leads for further drug development in oncology.
- Disrupting TLS via REV1 offers a viable strategy to enhance chemotherapy efficacy.
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