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.

Public Health Relevance

Cancer is a major health and society issue in the US. Novel cancer therapeutics are in great need. In this application, we propose to develop small molecule modulators of lamins as potential cancer therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA211866-03
Application #
9743764
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Amin, Anowarul
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Sanford-Crane, Hannah; Pejovic, Tanja; Xiao, Xiangshu (2018) Drugging homologous recombination: back to the future. Future Med Chem 10:1279-1281
Li, Bingbing X; Chen, Jingjin; Chao, Bo et al. (2018) Anticancer Pyrroloquinazoline LBL1 Targets Nuclear Lamins. ACS Chem Biol 13:1380-1387
Li, Bingbing X; Chen, Jingjin; Chao, Bo et al. (2018) A Lamin-Binding Ligand Inhibits Homologous Recombination Repair of DNA Double-Strand Breaks. ACS Cent Sci 4:1201-1210