Chemical Modulators of Nuclear Lamins

核层蛋白是已知的核结构成分的V型中间丝(IF)蛋白 位于内核膜下的片层。最近，Lamins被认为与核有关 新陈代谢，特别是DNA损伤修复过程。然而，潜在的分子机制是 很大程度上是未知的。解决这些机制的挑战之一是，我们缺乏适当的工具来 操纵这个系统，而不是基因敲除，完全去除蛋白质。在这方面，小 层粘连蛋白的分子调节器将为剖析DNA的潜在机制提供宝贵的工具 用层板修复损伤。Lamins参与DNA修复途径与研究结果一致 层粘连蛋白在癌细胞中的表达经常受到错误调控。DNA复制应激与活性氧 由于癌基因的激活，在癌细胞中普遍存在。因此，癌细胞不断地产生DNA 双链断裂(DSB)。为了让癌细胞存活，必须修复这些双链断裂。 因此，在癌症的发展过程中，癌细胞共同进化出有效的DSB修复 保护它们免受内源性DNA复制压力的机制。通过利用的独特功能 内源性DSB普遍存在于癌细胞中，这种疗法可能在癌症中提供选择性毒性 而不会损害正常细胞。因此，小分子层粘连蛋白调节剂也可以提供潜力 癌症治疗学。我们最近发现了一种名为LBL1的新化合物，它选择性地对 癌细胞。我们进一步发现LBL1选择性地与核纤层结合。在此应用程序中，我们建议使用 以下是进一步开发LBL1及其衍生物作为潜在抗乳腺癌药物的三个具体目标 并了解它们的作用机制：1)表征LBL1与Lamins之间的结合；2) 确定LBL1作为层粘连蛋白结合配体和抗乳腺癌药物的构效关系；3) 探讨LMNA和RAD51之间的动态相互作用机制以及LBL1如何对其进行调节 进程。

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.