# Small molecules targeting RuvBL complex for triple negative breast cancer

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $571,007

## Abstract

Abstract
The goal of this project is to develop small molecule modulators of RuvBL1/L2 complex as potential therapies
for triple negative breast cancer (TNBC) by targeting DNA double-strand breaks (DSB) repair pathways. TNBC
is a subgroup of breast cancer and is molecularly characterized by the lack of expression of estrogen receptor
(ER), progesterone receptor (PR) or HER2 (human epidermal growth factor receptor 2) amplification. DNA
replication stress and reactive oxygen species are prevalent in TNBC cells due to activation of various
oncogenes. Thus, TNBC cells constantly generate DSBs. In order for the TNBC cells to survive, these lethal
DSBs must be repaired. Accordingly, over the course of development of cancer, TNBC cells have co-evolved
efficient DSB repair mechanisms that protect them from the endogenous lethal DSBs. Therefore, targeting
DNA repair pathways has been proposed as a potentially powerful strategy to develop novel therapeutics for
TNBC. By exploiting this unique feature of endogenous DSBs prevalent only in TNBC cells, such therapeutics
can offer selective toxicity to TNBC cells without harming normal cells. We recently identified a novel small
molecule lead compound to target RuvBL1/L2 to inhibit DSB repair in TNBC cells. In this application, we
propose to further develop this small molecule lead compound for the treatment of TNBC with 3 specific aims.
In aim 1, we will study the mechanism of action of this novel lead compound. In aim 2, we will optimize this
lead compound using different medicinal chemistry strategies. In aim 3, we will investigate the optimized
compounds' anti-TNBC efficacy in different preclinical models alone and in combination with PARP inhibitors.

## Key facts

- **NIH application ID:** 10865018
- **Project number:** 5R01CA278058-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Bingbing Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $571,007
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865018

## Citation

> US National Institutes of Health, RePORTER application 10865018, Small molecules targeting RuvBL complex for triple negative breast cancer (5R01CA278058-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10865018. Licensed CC0.

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