# Inhibition of Translesion Synthesis as a Novel Strategy for Cancer Chemotherapy

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2020 · $507,872

## Abstract

Platinating and alkylating agents are standard first-line chemotherapy for many forms of human cancer.
Typically, patients initially respond well to these agents; however, many can develop resistance and experience
relapse, which requires a change in drug regimen to combat the relapsed cancer. In addition, the high doses of
these drugs required for their anti-cancer effects can result in toxic side effects in other tissues throughout the
body, limiting both the short- and long-term effectiveness of first-line agents. Translesion synthesis (TLS) is an
important mechanism through which proliferating cells tolerate DNA damage during replication without repairing
the damage. In the context of cancer treatment, TLS promotes survival of tumor cells by allowing replication over
platinum and alkyl DNA adducts, which results in increased mutations in surviving tumor cells and acquisition of
resistance to the first-line agent. Disruption of TLS sensitizes cancers to genotoxic agents and reduces
mutagenesis in tumors, suggesting that combination therapy with an inhibitor of TLS could enhance the efficacy
of first-line agents and prevent chemoresistance. As such, small molecule inhibitors of TLS are emerging as a
new class of adjuvant agents for first-line cancer chemotherapy.
 Assembly of the multi-protein complex that mediates TLS is controlled by the DNA polymerase Rev1, which
serves as the central scaffold to maintain the complex through multiple protein-protein interactions (PPIs).
Several essential steps of TLS are mediated through PPIs between the C-terminal domain of Rev1 (Rev1-CT)
and Rev-1 interacting regions (RIR) from multiple TLS DNA polymerases. Previous studies have demonstrated
that suppression of Rev1 expression in vitro and in vivo sensitizes cancer cells to genotoxic chemotherapeutics
and decreases acquired drug resistance in tumors. Recent collaborative research in our labs has led us to identify
the first reported small molecules that inhibit TLS by disrupting the Rev1-CT/RIR PPI through direct binding to
Rev1-CT at the RIR interface. These compounds increase cisplatin sensitivity and reduce cisplatin-induced
mutagenesis in human cancer cells. Our results demonstrate that the Rev1-CT/RIR interface is a druggable PPI
and they validate that its disruption enhances the anti-cancer effects of first-line genotoxic agents. Within this
context, the overall goal of our studies is to apply a comprehensive interdisciplinary approach to develop our
lead TLS inhibitors as a new class of anti-cancer therapeutics. In pursuit of this goal, we will undertake the
following specific aims: (1) synthesize and characterize improved small molecule inhibitors of the Rev1-CT/RIR
PPI, (2) evaluate Rev1-CT/RIR inhibitors using in vitro biochemical and structural approaches, (3) probe cellular
anti-TLS and anti-cancer activities of the Rev1-CT/RIR inhibitors, and (4) perform in vivo studies on optimal
compounds. We anticipate that these studies will identify small...

## Key facts

- **NIH application ID:** 9949677
- **Project number:** 5R01CA233959-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Matthew Kyle Hadden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $507,872
- **Award type:** 5
- **Project period:** 2019-06-10 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949677

## Citation

> US National Institutes of Health, RePORTER application 9949677, Inhibition of Translesion Synthesis as a Novel Strategy for Cancer Chemotherapy (5R01CA233959-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9949677. Licensed CC0.

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