Chemical Modulators of Nuclear Lamins

核纤层蛋白的化学调节剂

• 批准号: 10411359
• 负责人: Xiangshu Xiao
• 金额: $ 11.4万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411359
• 关键词: Address; Binding; Biochemical; Breast Cancer Cell; C-terminal; Cell Nucleus; Cells; Chemicals; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA biosynthesis; Data; Double Strand Break Repair; Exhibits; Genes; Genomic Instability; Goals; Health; Homologous Protein; Immunoglobulin Domain; Impairment; Intermediate Filament Proteins; Knock-out; LMNB1 gene; Lamin Type A; Lamins; Libraries; Ligand Binding; Malignant Neoplasms; Mammalian Cell; Metabolism; Molecular; Mutation; N-terminal; Nonhomologous DNA End Joining; Normal Cell; Nuclear; Nuclear Inner Membrane; Nuclear Lamin; Nuclear Lamina; Oncogene Activation; Other Genetics; Pathway interactions; Process; Proteins; RNA Splicing; Rad51 recombinase; Reactive Oxygen Species; Rod; Role; Series; Societies; Structure; Structure-Activity Relationship; System; TP53 gene; Therapeutic; Toxic effect; Variant; acyl group; base; biophysical techniques; cancer cell; chemoproteomics; course development; genetic approach; homologous recombination; malignant breast neoplasm; novel; repair function; repaired; replication stress; scaffold; small molecule; stress reactivity; tool

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.

核纤层蛋白是V型中间丝（IF）蛋白，已知是核纤层蛋白的结构组分。 位于内核膜下面的层。最近，核纤层蛋白被牵连到核 代谢，特别是DNA损伤修复过程。然而，潜在的分子机制是 大部分未知。处理这些机制的挑战之一是，我们缺乏适当的工具， 操纵这个系统而不是基因敲除，基因敲除完全去除蛋白质。对此，小 核纤层蛋白的分子调节剂将为剖析DNA的潜在机制提供宝贵的工具 由核纤层修复损伤。核纤层蛋白参与DNA修复途径与以下发现一致， 核纤层蛋白的表达经常在癌细胞中被错误调节。DNA复制应激与活性氧 由于致癌基因的激活，在癌细胞中普遍存在。因此癌细胞不断产生DNA 双链断裂（DSB）。这些DSB必须被修复才能让癌细胞存活。 因此，在癌症的发展过程中，癌细胞共同进化了有效的DSB修复 保护它们免受内源性DNA复制应激的机制。通过利用 内源性DSB在癌细胞中普遍存在，这样的治疗剂可以潜在地在癌症中提供选择性毒性。 不伤害正常细胞。因此，小分子核纤层蛋白调节剂也可以提供潜在的 癌症治疗学我们最近发现了一种名为LBL 1的新型化合物， 癌细胞我们进一步发现LBL 1选择性结合核纤层蛋白。在本申请中，我们提出 以下三个具体目标是进一步开发LBL 1及其衍生物作为潜在的抗乳腺癌药物 并了解其作用机制：1）表征LBL 1和核纤层蛋白之间的结合; 2） 确定LBL 1作为层粘连蛋白结合配体和抗乳腺癌剂的结构-活性关系; 3） 研究LMNA和Rad 51之间的动态相互作用机制以及LBL 1如何调节这种相互作用 过程