# Chemical Modulators of Nuclear Lamins

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $352,275

## Abstract

Nuclear lamins are type V intermediate filament (IF) proteins known to be structural components of nuclear
lamina that lie underneath the inner nuclear membrane. Recently, lamins have been implicated in nuclear
metabolism, in particular DNA damage repair process. However, the underlying molecular mechanisms are
largely unknown. One of the challenges to address these mechanisms is that we lack appropriate tools to
manipulate this system other than genetic knockouts, which remove the proteins entirely. In this regard, small
molecule modulators of lamins will provide invaluable tools to dissect the underlying mechanisms of DNA
damage repair by lamins. Lamins' involvement in DNA repair pathways is consistent with the findings that
expression of lamins is often misregulated in cancer cells. DNA replication stress and reactive oxygen species
are prevalent in cancer cells due to activation of oncogenes. Thus cancer cells constantly generate DNA
double-strand breaks (DSBs). These DSBs must be repaired in order for the cancer cells to survive.
Accordingly, over the course of development of cancer, cancer cells have co-evolved efficient DSB repair
mechanisms that protect them from endogenous DNA replication stress. By exploiting the unique feature of
endogenous DSBs prevalent in cancer cells, such therapeutics can potentially offer selective toxicity in cancer
cells without harming normal cells. Therefore, small molecule lamin modulators can also provide potential
cancer therapeutics. We recently discovered a novel compound called LBL1 that was selectively toxic to
cancer cells. We further found that LBL1 selectively binds to nuclear lamins. In this application, we propose the
following three specific aims to further develop LBL1 and its derivatives as potential anti-breast cancer agents
and understand their mechanism of action: 1) To characterize the binding between LBL1 and lamins; 2) To
define the structure-activity relationships of LBL1 as a lamin-binding ligand and an anti-breast cancer agent; 3)
To investigate the mechanism of dynamic interplay between LMNA and Rad51 and how LBL1 modulates this
process.

## Key facts

- **NIH application ID:** 10219173
- **Project number:** 5R01CA211866-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Xiangshu Xiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,275
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219173

## Citation

> US National Institutes of Health, RePORTER application 10219173, Chemical Modulators of Nuclear Lamins (5R01CA211866-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219173. Licensed CC0.

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