# Inhibiting Rev1-mediated translesion DNA synthesis for cancer therapy

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $521,760

## Abstract

Project Summary/Abstract
 Prostate cancer is a leading cause of cancer death in American men. The National Cancer Institute estimated
that there would be ~268,490 new cases of prostate cancer and ~34,500 deaths from prostate cancer within the
United States for 2022. Despite the development of second-generation hormonal therapies (e.g., enzalutamide)
and targeted poly(ADP-ribose) polymerase (PARP) inhibitors (e.g., olaparib), the mortality of prostate cancer
remains high as intrinsic and acquired drug resistance is common to all these agents, and many patients develop
incurable metastatic castration-resistant prostate cancer (mCRPC) within 2–3 years.
 Accumulating evidence and our preliminary data show that mCRPC cells deficient in homologous
recombination repair (HRR) activities due to genetic mutations of DNA repair genes, such as BRCA1/2, or due
to the enzalutamide treatment-induced BRCAness state are particularly vulnerable to disruption of DNA-damage
tolerance pathways, such as the mutagenic translesion DNA synthesis (TLS). TLS is a fundamental cellular
defense mechanism that enables DNA replication across lesion sites under replication stress in order to promote
cell survival at the cost of replication fidelity.
 The eukaryotic Y-family polymerase Rev1 is an essential scaffolding protein in TLS, and the interaction
between its C-terminal domain (CTD) with translesion polymerase z is absolutely required for function. Aided by
our structural elucidation of the Rev1-bridged translesionsome complex in TLS, we have identified the first-in-
class in vivo active small molecule inhibitor, JH-RE-06, that disrupts TLS by directly binding to the Rev1 CTD to
block the Rev1 interaction with the Rev7 component of polymerase z. JH-RE-06 suppresses spontaneous and
treatment-induced mutagenesis in cells and sensitizes cancer cells to a variety of DNA-damaging agents both
in vitro and in a murine xenograft tumor model. Recently, we have shown that mCRPC cells in the BRCAness
state are particularly vulnerable to JH-RE-06 inhibition. The goal of this proposal is to further characterize JH-
RE-06 and derivatives in prostate cancer cells, optimize their potency, safety, and other pharmacological
properties, and demonstrate their effectiveness in treating mCRPC and suppressing acquired drug resistance in
murine tumor models. The successful execution of the proposal will profoundly alter the existing paradigm of
lethal prostate cancer treatment by providing effective means to overcome intrinsic and acquired drug resistance,
thus improving the outcomes for patients with lethal prostate cancer.

## Key facts

- **NIH application ID:** 10807991
- **Project number:** 1R01CA279034-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jiyong Hong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $521,760
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807991

## Citation

> US National Institutes of Health, RePORTER application 10807991, Inhibiting Rev1-mediated translesion DNA synthesis for cancer therapy (1R01CA279034-01A1). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/10807991. Licensed CC0.

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