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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肺癌是美国和全世界男性和女性癌症相关死亡的主要原因。全球每年有超过40万人死于肺癌，其中肺鳞癌癌(LUSC)约占30%。然而，尚无针对 LUSC 的有效治疗方法。 LUSC 是一种以多种 DNA 改变为特征的非小细胞肺癌 (NSCLC)，包括 3q26 染色体片段频繁扩增。 3q26 片段值得注意，因为它包含 YEATS 结构域包含 2 (YEATS2) 基因，该基因在许多人类中经常被扩增癌症，包括 LUSC (~50%)、卵巢癌 (28%)、头颈癌 (25%) 和食道癌 (25%)。高的 YEATS2 mRNA 表达与 NSCLC 患者的不良预后相关，表明 YEATS2 可能具有促肿瘤作用。 YEATS2 是 Ada-Two-A-Containing (ATAC) 复合物的化学计量亚基，ATAC 复合物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 结构域。我们先前表明，YEATS2 的 YEATS 结构域可作为组蛋白乙酰化和其他组蛋白酰化的类型，例如巴豆酰化。重要的是，破坏 YEATS 组蛋白读取活动损害 YEATS2 和 ATAC 复合体的正常功能，导致组蛋白乙酰化减少，降低靶基因表达，抑制NSCLC细胞生长和存活。这些数据证明 YEATS2 的 YEATS 结构域是一个潜在的药物靶点，并且靶向 YEATS2 可能提供治疗 NSCLC 和以 YEATS2 为特征的其他类型癌症的治疗方法放大。该提案的目的是开发针对组蛋白酰化结合的有效且特异性的抑制剂 YEATS2 的 YEATS 结构域的活性。为此，我们将 (1) 进行高通量筛选来识别 YEATS2 小分子抑制剂，以及 (2) 在体外和细胞基础上评估和表征命中化合物化验。通过拟议的研究，我们期望鉴定出有效的、特定的 YEATS2 YEATS 结构域化学物质不同化学型的探针。这些化合物将为进一步开发小型化提供基础。用于靶向治疗的分子。同样，研究界将能够使用这些新抑制剂作为了解 YEATS2 在人类癌症中的功能和机制的重要工具。