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

• 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
• 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

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.

新出现的证据表明，蛋白质乙酰转移酶在多种疾病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n端 乙酰基转移酶D（NatD），也称为Naa 40、Nat 4或Patt 1，是蛋白质中的一个独特成员 N-末端乙酰转移酶，因为它只乙酰化组蛋白H2 A和H4， SGRGK的相同N末端序列。据报道，NatD在一个 多种过程，包括染色质结构重塑、细胞迁移和侵袭，以及 凋亡人肺癌和结直肠癌组织中NatD水平升高与 临床效果差。此外，NatD的缺失抑制了人肺癌细胞的侵袭， 降低结肠直肠癌异种移植小鼠模型中的肿瘤生长。因此，我们假设 NatD是开发新型肺癌治疗药物的一个引人注目的靶点， 结肠直肠癌然而，没有特异性小分子探针可用于NatD， 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 目的是发现新的，有效的，选择性的小分子NatD抑制剂。对于该应用， 我们将采用一系列简便和可重复的高通量筛选（HTS）试验， 正交读数，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。然后我们将描述 活性化合物的结构，机制，选择性和细胞为基础的研究。完成后 在这个项目中，我们期望鉴定出有效的和选择性的一流的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调节剂的开发和我们对NatD调节的理解， 癌症患者的路径。