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：
10366567
负责人：
Rong Huang
金额：
$ 55.97万
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/10366567
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 Crystallization Development Epigenetic Process Fibroblasts Fluorescence Fluorescence Polarization Fluorescent Probes Foundations Genomics Goals H1299 HCT116 Cells Histone H2A Histone H4 Human Institutes Investigation Knowledge Lung Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Mission Mitochondria Molecular Monitor N-terminal Outcome Pathway interactions Peptides Pharmacology Physiological Play Process Proteins Public Health Radioactive Reporting Reproducibility Research Resources Roentgen Rays Role Sampling Series Structure Structure-Activity Relationship System TP53 gene Testing Tetracyclines Therapeutic Tissues Titrations Up-Regulation Xenograft procedure adduct analog base cancer cell cell motility chromatin remodeling cyanine dye 5 drug discovery epithelial to mesenchymal transition fluorophore high throughput screening human disease inhibitor knock-down lung cancer cell member mouse model novel novel therapeutic intervention pharmacophore prevent response screening slug small hairpin RNA small molecule small molecule inhibitor small molecule libraries stable cell line success therapeutic target transcription factor tumor growth tumor progression

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.

新的证据表明蛋白质乙酰转移酶在多种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，因为它仅乙酰化具有相同结构的组蛋白 H2A 和 H4 SGRGK 的 N 端序列相同。据报道，NatD 在多种过程，包括染色质结构重塑、细胞迁移和侵袭，以及细胞凋亡。人肺癌和结直肠癌组织中 NatD 水平升高与临床结果不佳。此外，NatD 的缺失会抑制人肺癌细胞的侵袭和减少结直肠癌异种移植小鼠模型中的肿瘤生长。因此，我们假设 NatD 是开发新型肺癌和癌症疗法的引人注目的目标结直肠癌。然而，目前尚无特定的小分子探针可供 NatD 检测。破译 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型、有效、选择性的小分子 NatD 抑制剂。对于这个应用程序，我们将采用一系列简便且可重复的高通量筛选（HTS）检测正交读数可从选定的化学库中筛选 400,000 种不同的化合物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、机制、选择性和细胞研究中的活性化合物。完成后在这个项目中，我们期望鉴定出有效且选择性一流的 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速 NatD 调节剂的开发以及我们对 NatD 调节的理解癌症患者的途径。