High Throughput Screen for Inhibitors of the YEATS2 Histone Acylation Reader

YEATS2 组蛋白酰化酶抑制剂的高通量筛选

• 批准号: 10551322
• 负责人: Xiaobing Shi
• 金额: $ 43.09万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-14 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551322
• 关键词: 3q26; Acylation; Apoptosis; Binding; Biological Assay; Calorimetry; Cancer Etiology; Cancer Patient; Cell Survival; Cells; Cessation of life; ChIP-seq; Characteristics; Chemicals; Chromatin; Communities; Complex; DNA Sequence Alteration; DNA-Protein Interaction; Data; Development; Drug Targeting; Ensure; Evolution; Fluorescence Polarization; Gene Expression; Genes; Head and neck structure; Histone Acetylation; Histone H3; Histones; Human; Impairment; In Vitro; Interferometry; Lead; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Measurement; Measures; Non-Small-Cell Lung Carcinoma; Ovarian; Peptides; Permeability; Pharmaceutical Preparations; Prognosis; Proliferating; Proteins; Reader; Reading; Research; Role; Series; Squamous Cell Lung Carcinoma; Technology; Testing; Therapeutic; Titrations; Tumor Promotion; Validation; Woman; cancer type; cell growth; effective therapy; flexibility; high throughput screening; histone acetyltransferase; inhibitor; lung cancer cell; mRNA Expression; men; meter; novel; response; scaffold; small molecule; small molecule inhibitor; small molecule libraries; targeted treatment; tool; transcriptome sequencing

PROJECT SUMMARY Lung cancer is the leading cause of cancer-related deaths in both men and women in the U.S and worldwide. There are more than 400,000 deaths of lung cancer worldwide each year, among which lung squamous cell carcinoma (LUSC) accounts for about 30%. However, no effective treatments for LUSC are available. LUSC is one type of non-small cell lung cancer (NSCLC) characterized by numerous DNA alterations, including frequent amplification of the 3q26 chromosomal segment. The 3q26 segment is noteworthy because it contains the YEATS domain containing 2 (YEATS2) gene, a gene that is frequently amplified in a number of human cancers, including LUSC (~50%), ovarian (28%), head and neck (25%), and esophagus cancers (25%). High YEATS2 mRNA expression is associated with a poor prognosis of NSCLC patients, indicating that YEATS2 may have a tumor-promoting role. YEATS2 is a stoichiometric subunit of the Ada-Two-A-Containing (ATAC) complex, a conserved metazoan histone acetyltransferase (HAT) complex. YEATS2 contains an evolutionally conserved YEATS domain. We previously showed that the YEATS domain of YEATS2 functions as a reader of histone acetylation and other types of histone acylation such as crotonylation. Importantly, disrupting the YEATS histone reading activity impairs the normal functions of YEATS2 and the ATAC complex, resulting in reduced histone acetylation, decreased target gene expression, and inhibition of cell growth and survival of NSCLC. These data demonstrate that the YEATS domain of YEATS2 is a potential drug target, and that targeting YEATS2 may provide a therapeutic approach for treating NSCLC and other types of cancer characterized by YEATS2 amplification. The objective of this proposal is to develop potent and specific inhibitors targeting the histone acylation binding activity of the YEATS domain of YEATS2. For this, we will (1) conduct a high-throughput screen to identify YEATS2 small-molecule inhibitors, and (2) evaluate and characterize hit compounds in in vitro and cell-based assays. Through the proposed studies, we expect to identify potent, specific YEATS2 YEATS domain chemical probes of different chemotypes. These compounds will provide the basis for further development of small molecules for targeted therapies. Likewise, the research community will be able to use these new inhibitors as important tools to understand the functions and mechanisms of YEATS2 in human cancers.

项目摘要 肺癌是美国和全世界男性和女性与癌症相关死亡的主要原因。 全世界在全球有40万多人死亡，其中肺部鳞状细胞中有超过40万例 癌（LUSC）约占30％。但是，没有有效的LUSC治疗方法。 Lusc是 一种类型的非小细胞肺癌（NSCLC），其特征是多种DNA改变，包括 3q26染色体节段的频繁扩增。 3Q26段值得注意，因为它包含 包含2（Yeats2）基因的Yeats结构域，该基因经常在许多人类中得到扩增 包括LUSC（约50％），卵巢（28％），头颈（25％）和食道癌（25％）在内的癌症。高的 Yeats2 mRNA表达与NSCLC患者的预后不良有关，表明Yeats2 可能具有促进肿瘤的作用。 Yeats2是ADA-TWO-A-TWO-A（ATAC）配合物的化学计量亚基，这是一种保守的后生动物 组蛋白乙酰转移酶（HAT）复合物。 Yeats2包含一个进化保守的Yeats域。我们 以前表明，Yeats2的Yeats结构域是组蛋白乙酰化和其他的读取器 组蛋白酰化的类型，例如共依氨酸化。重要的是，破坏叶芝组蛋白阅读活动 损害Yeats2和ATAC复合物的正常功能，导致组蛋白乙酰化降低， 靶基因表达降低，抑制NSCLC的细胞生长和存活。这些数据 证明Yeats2的Yeats域是一个潜在的药物靶标，而针对Yeats2可能 提供一种治疗NSCLC和其他类型的癌症的治疗方法 放大。 该建议的目的是开发针对组蛋白酰化结合的有效和特定的抑制剂 Yeats2的Yeats域的活性。为此，我们将（1）进行高通量屏幕以识别 Yeats2小分子抑制剂，（2）评估和表征基于细胞和细胞的HIT化合物 测定。通过拟议的研究，我们希望确定有效的，特定的Yeats2 Yeats域化学 探针的探针不同。这些化合物将为进一步开发小型提供基础 靶向疗法的分子。同样，研究界将能够使用这些新抑制剂作为 了解人类癌症中Yeats2的功能和机制的重要工具。