Targeting the ENL YEATS domain for the development of anti-leukemia agents

靶向 ENL YEATS 结构域用于开发抗白血病药物

• 批准号: 10534219
• 负责人: Wenshe Ray Liu
• 金额: $ 16.92万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-03 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534219
• 关键词: Acetylation; Acute Myelocytic Leukemia; Amides; Amidines; Amines; Automobile Driving; Binding; Blood Cells; Cell Line; Cells; Charge; Chemical Structure; Chimeric Proteins; Chromatin; Chromosomal translocation; Complex; Computer Assisted; Crystallography; Development; Disease; Docking; Drug Targeting; Energy Transfer; Epigenetic Process; Exhibits; Gene Expression; Generations; Genes; Goals; Growth; Health Promotion; Hematologic Neoplasms; Histone Acetylation; Histones; Human; Impairment; Knowledge; Length; Leukemic Cell; Ligands; Luciferases; Lysine; MLL gene; MLLT3 gene; Maintenance; Methods; Mission; Mixed-Lineage Leukemia; Modeling; Myeloid Cells; Nature; Peptides; Permeability; Pharmaceutical Preparations; Positioning Attribute; Proliferating; Protac; Proteins; Public Health; Reader; Research; Role; Series; Signal Transduction; Sodium Chloride; Structure-Activity Relationship; System; Tertiary Protein Structure; Testing; Therapeutic; Time; Tracer; Ubiquitination; United States National Institutes of Health; X-Ray Crystallography; antileukemic agent; design; drug discovery; flexibility; fluorophore; functional group; high throughput screening; improved; inhibitor; leukemia; novel; preclinical evaluation; programs; research clinical testing; residence; screening; simulation; small molecule; small molecule inhibitor; small molecule libraries; success; targeted treatment; therapeutic development; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a hematological cancer characterized by the quick proliferation and accumulation of immature myeloid cells that are impaired to differentiate into normal blood cells. As one of the deadliest subtypes of leukemia, AML is often driven by chromosomal translocations that fuse the multiple lineage leukemia gene MLL1 to either of the YEATS domain-containing proteins, ENL or AF9. Recent studies have indicated that ENL but not AF9 is essential for the maintenance of MLL-rearranged leukemia cells, making ENL as a valuable target for the development of therapeutics for AML. The ENL YEATS domain serves a critical role in the recognition of histone lysine acetylation in chromatin. By developing small molecules that selectively target the ENL YEATS domain to inhibit its recognition of histone acetylation in chromatin, multiple compounds have been identified that inhibit the growth of MLL-rearranged leukemia cells. Encouraged by this strong preliminary study, the current application is focused on expanding the drug discovery endeavor in targeting ENL for the development of MLL-rearranged leukemia therapeutics by pursuing three short-term specific aims. In the first aim, NanoBRET systems will be developed for ENL and its close paralogue AF9 for the analysis of ENL inhibitors in their cellular permeability, stability, selectivity, and drug residence time in cells. In the second aim, thorough characterization of developed small molecule ENL inhibitors will be conducted and obtained knowledge will be used for the development of novel inhibitors with improved potency and selectivity. In the third aim, a currently booming drug discovery concept, proteolysis targeting chimera (PROTAC), will be applied to the ENL drug discovery effort for the development of ENL-targeting PROTAC molecules. The success of the project will make a number of potential MLL-rearranged leukemia therapeutics available for further preclinical and clinical evaluations.

项目总结/摘要 急性髓系白血病（AML）是一种血液系统癌症，其特征在于快速增殖， 未成熟的骨髓细胞聚集，不能分化成正常的血细胞。为一体的 作为白血病最致命的亚型，AML通常由染色体易位引起， 白血病基因MLL 1与含YEATS结构域的蛋白ENL或AF 9中的任一种结合。最近的研究 表明ENL而不是AF 9对于维持MLL重排的白血病细胞是必需的，使得ENL 作为开发AML治疗剂的有价值的靶点。ENL YEATS域名在 识别染色质中的组蛋白赖氨酸乙酰化。通过开发选择性靶向 ENL YEATS结构域抑制其识别染色质中的组蛋白乙酰化，多个化合物具有 已被鉴定为抑制MLL重排白血病细胞的生长。在这种强烈的初步鼓励下 研究，目前的应用集中在扩大药物发现的奋进，在靶向ENL的 通过追求三个短期特定目标来开发MLL重排白血病疗法。上 目的是为ENL及其近缘蛋白AF 9开发NanoBRET系统，用于分析ENL抑制剂 它们的细胞渗透性、稳定性、选择性和药物在细胞中的停留时间。在第二个目标，彻底 将对开发的小分子ENL抑制剂进行表征，并将获得的知识 用于开发具有改进的效力和选择性的新型抑制剂。在第三个目标中，目前 一种新兴的药物发现概念--蛋白水解靶向嵌合体（PROTAC）将被应用于ENL药物 开发ENL靶向PROTAC分子的发现努力。该项目的成功将使 许多潜在的MLL重排白血病治疗剂可用于进一步的临床前和临床 评价。