Discovery of small molecule inhibitors for protein N-terminal acetyltransferase D

蛋白质 N 末端乙酰转移酶 D 小分子抑制剂的发现

基本信息

批准号：
10532369
负责人：
Rong Huang
金额：
$ 56万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10532369
关键词：
A549 Acetylation Acetyltransferase Active Sites Address Affinity Antibodies Apoptosis Binding Biochemical Biological Biological Assay Biological Process CASP9 gene Calorimetry Cancer Patient Cancer cell line Cell Proliferation Cell Survival Cell physiology Cells Chemicals Chromatin Structure Clinical Coenzyme A Collection Colon Colorectal Cancer Complex Development Epigenetic Process Fibroblasts Fluorescence Fluorescence Polarization Fluorescent Probes Foundations Genomics Goals H1299 HCT116 Cells HT29 Cells Histone Acetylation Histone H2A Histone H4 Human Invaded Investigation Knowledge Lung Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Mission Mitochondria Molecular Monitor N-terminal Outcome Pathway interactions Peptides Physiological Play Process Proteins Public Health Radioactive Reporting Reproducibility Research Resources Roentgen Rays Role Sampling Series Slug protein Structure Structure-Activity Relationship System TP53 gene Testing Tetracyclines Therapeutic Tissues Titrations Up-Regulation Xenograft procedure adduct analog cancer cell cell motility chromatin remodeling cyanine dye 5 drug discovery epithelial to mesenchymal transition fluorophore gene repression high throughput screening human disease inhibitor knock-down lung cancer cell member meter mouse model novel novel therapeutic intervention pharmacologic pharmacophore prevent redshift response screening small hairpin RNA small molecule small molecule inhibitor small molecule libraries stable cell line success therapeutic target tumor growth tumor progression

A549 Acetylation Acetyltransferase Active Sites Address Affinity Antibodies Apoptosis Binding Biochemical Biological Biological Assay Biological Process CASP9 gene Calorimetry Cancer Patient Cancer cell line Cell Proliferation Cell Survival Cell physiology Cells Chemicals Chromatin Structure Clinical Coenzyme A Collection Colon Colorectal Cancer Complex Development Epigenetic Process Fibroblasts Fluorescence Fluorescence Polarization Fluorescent Probes Foundations Genomics Goals H1299 HCT116 Cells HT29 Cells Histone Acetylation Histone H2A Histone H4 Human Invaded Investigation Knowledge Lung Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Mission Mitochondria Molecular Monitor N-terminal Outcome Pathway interactions Peptides Physiological Play Process Proteins Public Health Radioactive Reporting Reproducibility Research Resources Roentgen Rays Role Sampling Series Slug protein Structure Structure-Activity Relationship System TP53 gene Testing Tetracyclines Therapeutic Tissues Titrations Up-Regulation Xenograft procedure adduct analog cancer cell cell motility chromatin remodeling cyanine dye 5 drug discovery epithelial to mesenchymal transition fluorophore gene repression high throughput screening human disease inhibitor knock-down lung cancer cell member meter mouse model novel novel therapeutic intervention pharmacologic pharmacophore prevent redshift response screening small hairpin RNA small molecule small molecule inhibitor small molecule libraries stable cell line success therapeutic target tumor growth tumor progression

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项目摘要

Emerging evidence implies that protein acetyltransferases play a crucial role in diverse biological processes and various human diseases including cancer. Protein N-terminal acetyltransferase D (NatD), also known as Naa40, Nat4, or Patt1, is a unique member of protein N-terminal acetyltransferases because it only acetylates histones H2A and H4 that share the identical N-terminal sequence of SGRGK. NatD has been reported to play an important role in a variety of processes including remodeling of chromatin structure, cell migration and invasion, and apoptosis. The elevated level of NatD in human lung and colorectal cancer tissues correlates with poor clinical outcomes. Moreover, loss of NatD suppresses human lung cancer cell invasion and decreases the tumor growth in colorectal cancer xenograft mice models. Hence, we hypothesize that NatD is a compelling target for the development of novel cancer therapeutics for lung and colorectal cancers. However, there are no specific small molecule probes available for NatD to decipher the functions of NatD acetyltransferase activity in cancer. To fill this gap, our long-term goal is to discover novel, potent, and selective small molecule NatD inhibitors. For this application, we will employ a series of facile and reproducible high-throughput screening (HTS) assays with orthogonal readouts to screen 400,000 diverse compounds from selected chemical libraries at the Chemical Genomics Facility at Purdue Institute for Drug Discovery. Then we will characterize active compounds in structural, mechanistic, selectivity, and cell-based studies. Upon completion of this project, we expect to identify potent and selective first-in-class NatD small molecule inhibitors as chemical probes for NatD function in cells. The knowledge gained from this project would expedite the development of NatD modulators and our understanding of NatD-regulated pathways in cancer patients.

新兴的证据表明，蛋白质乙酰转移酶在多样化中起着至关重要的作用生物过程和包括癌症在内的各种人类疾病。蛋白质N末端乙酰基转移酶D（NATD），也称为NaA40，Nat4或Patt1，是蛋白质的独特成员 N末端乙酰转移酶，因为它仅乙酰化组蛋白H2a和H4共享 SGRGK的N末端序列相同。据报道，NATD在各种过程，包括重塑染色质结构，细胞迁移和侵袭以及凋亡。人肺和结直肠癌组织中NATD水平升高与临床结果不佳。此外，NATD的丧失会抑制人类肺癌细胞的侵袭和减少结直肠癌异种移植小鼠模型的肿瘤生长。因此，我们假设 NATD是开发新型肺癌治疗剂的引人注目的目标结直肠癌。但是，NATD没有特定的小分子探针解读NATD乙酰转移酶活性在癌症中的功能。为了填补这一空白，我们的长期目标是发现新颖，有效和选择性的小分子NATD抑制剂。对于此应用程序，我们将使用一系列便利和可重复的高通量筛选（HTS）测定从选定的化学库中筛选400,000种不同化合物的正交读数普渡大学药物发现研究所的化学基因组学设施。然后我们将表征结构，机械，选择性和基于细胞的研究中的活性化合物。完成后在这个项目中，我们希望确定有效和选择性的一流的NATD小分子抑制剂作为细胞中NATD功能的化学探针。从这个项目中获得的知识将加快NATD调制器的开发以及我们对NATD调节的理解癌症患者的途径。