Identification of LSD1 inhibitors targeting epigenetic regulation in tumor cells

针对肿瘤细胞表观遗传调控的 LSD1 抑制剂的鉴定

基本信息

批准号：
8444579
负责人：
Patrick M Woster
金额：
$ 23.26万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444579
关键词：
Active Sites Affinity Amino Acids Animals Azacitidine Biguanides Binding Biological Biological Assay Carcinoma Catalytic Domain Cell Survival Cell physiology Chemicals Chromatin Colon Carcinoma Colonic Adenoma Computer Simulation Cultured Tumor Cells DNA Methyltransferase Inhibitor Data Databases Development Dose Enzymes Epigenetic Process Evaluation Family GATA4 transcription factor Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Goals Guanidines HCT116 Cells Histone Deacetylase Inhibitor Histone H3 Homologous Gene Human In Situ In Vitro Inhibitory Concentration 50 Kinetics Lead Lethal Dose 50 Libraries Lysine MS-275 Malignant Epithelial Cell Malignant Neoplasms Measures Methyltransferase Molecular Weight Monitor Monoamine Oxidase A Monoamine Oxidase B Monoamine Oxidase Inhibitors Mus Nitrogen Nude Mice Outcome Oxidases Peptides Pharmaceutical Chemistry Play Probability Proteins Publishing Recombinants Regulation Reporting Role Route Sequence Homology Series Specificity Structure Tranylcypromine Trichostatin A Tumor Cell Line Tumor Suppressor Genes Tumor Suppressor Proteins Xenograft Model abstracting analog antitumor agent base cell growth chemical synthesis chemotherapeutic agent chromatin modification chromatin remodeling cyclopropylamine demethylation design high throughput screening human lysine specific demethylase 1 in vivo inhibitor/antagonist lysine analog neoplastic cell new therapeutic target peptidomimetics polyamine oxidase preclinical study promoter research study screening small molecule libraries tumor growth tumor initiation tumor xenograft tumorigenesis virtual

项目摘要

Abstract. The recent discovery of the enzyme lysine-specific demethylase 1 (LSD1) has illuminated an important cellular mechanism for epigenetic control of gene expression. In particular, dimethyl lysine 4, histone H3 (H3K4me2) is a transcription activating chromatin mark at gene promoters, and aberrant demethylation of this mark by LSD1 may broadly repress the expression of tumor suppressor genes that are important in human cancer. We and others have conducted studies verifying that LSD1 is an exciting new therapeutic target. We recently reported a series of (bis)guanidines and (bis)biguanides that are potent inhibitors of recombinant human LSD1. These inhibitors significantly increase H3K4me2 levels, initiate chromatin remodeling and induce the re-expression of tumor suppressor genes, making them suitable leads for analogue development. We were the first to demonstrate antitumor effects of LSD1 inhibitors in vitro and have recently demonstrated their significant antitumor effects in vivo. These studies provide proof or principle that inhibition of LSD1 can lead to significant antitumor effects. The central hypothesis of this proposal is that compounds that inhibit LSD1 can be identified and developed for use in the treatment of human cancer. Along these lines, the specific aims of this proposal are: Specific aim 1. Design and synthesis of multiple series of analogues as potential inhibitors of LSD1. We will use a systematic medicinal chemistry approach that includes analogue synthesis and high-throughput evaluation to produce rationally designed libraries of small-molecule LSD1 inhibitors. These analogues will be structurally related to our lead compounds, or to the LSD1 substrate. We will also use virtual screening to identify leads from commercial databases, and to suggest more potent analogues for synthesis and screening. Specific aim 2. Evaluation of newly synthesized analogues as LSD1 inhibitors and study of their epigenetic effects in cultured tumor cells. Each analogue will be evaluated as an inhibitor of purified LSD1, and the kinetics of inhibition will be determined. The cellular effects of all analogues will be monitored in the HCT116 tumor cell line. Each compound will be evaluated alone, and in combination with a DNA methyltransferase inhibitor and/or a class I/II histone deacetylase inhibitor. We will monitor specific chromatin marks and gene products to determine whether each compound causes tumor suppressor gene re-expression, and cell growth and viability will be measured. Specific aim 3. Evaluation of LSD1 inhibitors and combination treatments in vivo. Promising compounds and combination treatments will be advanced to dosing and efficacy studies in human HCT116 tumor xenografts. Using this approach, there is a high probability of identifying potent LSD1 inhibitors that have the potential to become an important new class of antitumor agent.

抽象的。最近发现的赖氨酸特异性去甲基酶 1 (LSD1) 阐明了基因表达表观遗传控制的重要细胞机制。特别地，二甲基赖氨酸4，组蛋白 H3 (H3K4me2) 是基因启动子处的转录激活染色质标记，并且异常 LSD1对该标记的去甲基化可能会广泛抑制肿瘤抑制基因的表达这对于人类癌症很重要。我们和其他人进行了研究，证实 LSD1 是一种令人兴奋的新治疗目标。我们最近报道了一系列（双）胍和（双）双胍是重组人 LSD1 的有效抑制剂。这些抑制剂显着增加 H3K4me2 水平，启动染色质重塑并诱导肿瘤抑制基因的重新表达，使得它们适合模拟开发。我们是第一个证明其抗肿瘤作用的人 LSD1 抑制剂最近在体外证明了其显着的体内抗肿瘤作用。这些研究提供了证据或原理，证明抑制 LSD1 可以产生显着的抗肿瘤作用。这该提案的中心假设是可以鉴定抑制 LSD1 的化合物并开发用于治疗人类癌症。沿着这些思路，本次会议的具体目标提案如下：具体目标 1. 设计和合成多个系列的潜在类似物 LSD1抑制剂。我们将使用系统的药物化学方法，包括类似物合成和高通量评估以产生合理设计的小分子文库 LSD1 抑制剂。这些类似物在结构上与我们的先导化合物或 LSD1 相关基材。我们还将使用虚拟筛选来识别商业数据库中的线索，并建议用于合成和筛选的更有效的类似物。具体目标2.新评估合成类似物作为 LSD1 抑制剂并研究其在培养肿瘤细胞中的表观遗传效应。每个类似物将作为纯化 LSD1 的抑制剂进行评估，抑制动力学为决定。所有类似物的细胞效应将在 HCT116 肿瘤细胞系中进行监测。每个化合物将单独进行评估，并与 DNA 甲基转移酶抑制剂和/或 I/II 类组蛋白脱乙酰酶抑制剂。我们将监测特定的染色质标记和基因产物，以确定每种化合物是否会导致肿瘤抑制基因重新表达以及细胞生长和将测量生存能力。具体目标 3. LSD1 抑制剂和联合治疗的评价体内。有前景的化合物和联合治疗将进一步推进剂量和疗效人类 HCT116 肿瘤异种移植物的研究。使用这种方法，很有可能鉴定出有潜力成为重要的新型抗肿瘤药物的强效 LSD1 抑制剂代理人。