Discovery of small molecules targeting the histone acetylation reader ENL

发现针对组蛋白乙酰化阅读器 ENL 的小分子

• 批准号: 10311523
• 负责人: Hong Wen
• 金额: $ 43.97万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-12-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311523
• 关键词: Acetylation; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adult; Automation; Binding; Biochemical; Biological Assay; Biophysics; Calorimetry; Cell Line; Cells; ChIP-seq; Characteristics; Child; Childhood Leukemia; Chimeric Proteins; Chromatin; Chromosomal translocation; Complex; Development; Disease; Drug Design; Evolution; Exhibits; Fluorescence Polarization; Future; Gene Expression; Gene Expression Regulation; Gene Rearrangement; Goals; Growth; Histone Acetylation; Histone H3; Histones; Human; In Vitro; Infant; Lead; Leukemic Cell; Lysine; MLL gene; MLLT3 gene; Maintenance; Measurement; Methylation; Methyltransferase; Mixed-Lineage Leukemia; Molecular; Nature; Neonatal Leukemia; Oncogenic; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Prognosis; Reader; Reading; Series; Structure; Testing; Therapeutic; Titrations; Triage; Validation; base; cytotoxicity test; disorder subtype; driver mutation; drug development; effective therapy; gene translocation; genome-wide; high throughput screening; histone methyltransferase; in vivo; inhibitor; innovation; leukemia; preclinical study; response; scaffold; small molecule; small molecule inhibitor; small molecule libraries; standard care; synergism; targeted treatment; tool; transcriptome; treatment strategy

PROJECT SUMMARY The mixed-lineage leukemia (MLL) gene rearrangements account for approximately 80% of infant acute lymphoblastic leukemia (ALL) and 35-50% of infant acute myeloid leukemia (AML). Patients bearing rearrangements of the MLL gene are associated with dismal prognosis and particularly poor response to standard treatments. Up-to-date, effective therapies for this subtype of fatal disease are still lacking. Molecularly, inter-chromosomal translocations of MLL lead to in frame fusions of the N-terminus of MLL to the C-terminus of various fusion partners, which are known as the “driver” lesions of the diseases. Among more than 70 MLL fusion partners, a small subset of fusions account for most leukemogenic cases. In ALL, over 90% MLL rearrangements involve only four fusion partners: AFF1, AF9, ENL, and AF10, all are components of the super elongation complex (SEC) or the complex of the histone H3K79 methyltransferase DOT1L. It is believed that these MLL fusions share a common pathway by “hijacking” SEC or the DOT1L complex to promote aberrant activation of the target genes of MLL fusions, leading to the pathogenesis of leukemias. Studies from the applicant and others have demonstrated that ENL, a stoichiometric component of SEC and the DOT1L complex, is critical for the oncogenic function of the MLL-fusions. ENL contains an evolutionally conserved YEATS domain. The applicant found that the YEATS domain of ENL functions as a reader of histone acetylation (Cell, 2014, 159:558-71). Importantly, the acetylation reading function of the YEATS domain is essential for growth and survival of the MLL-rearranged leukemic cells (Nature, 2017, 543:265-269). These key findings provide the proof of concept that targeting the YEATS domain of ENL is a potentially valuable therapeutic option in treatment of MLL-rearranged leukemias. The goal of this proposal within the scope of this FOA is to develop potent and selective inhibitors of the ENL YEATS domain. The specific aims of the proposal are to (1) conduct a high-throughput screening for ENL small-molecule inhibitors; (2) validate and evaluate candidate hits by orthogonal assays; and (3) characterize hits in cell-based assays. The inhibitors obtained from the proposed study will serve as tool compounds to study the functions and mechanisms of ENL in promoting MLL-fusion proteins in gene regulation and disease maintenance. These compounds will also provide the basis for further development of small molecules for targeted therapies of MLL-translocated leukemias. Preclinical studies suggest that BET inhibitors exhibit limited efficacy as single agents. Selective and potent ENL inhibitors provided by this project will be an important tool to test the synergistic effect of ENL and BET inhibitions, providing an innovative therapeutic strategy for the treatment of MLL-rearranged leukemias.

项目摘要 混合系白血病（MLL）基因重排约占婴儿急性白血病的80%。 淋巴母细胞白血病（ALL）和35-50%的婴儿急性髓细胞白血病（AML）。患者轴承 MLL基因的重排与预后不良有关，尤其是对 标准治疗。迄今为止，仍然缺乏针对这种致命疾病亚型的有效疗法。 分子上，MLL的染色体间易位导致MLL的N-末端与MLL的N-末端的框内融合。 各种融合伴侣的C-末端，其被称为疾病的“驱动”病变。个以上的 超过70种MLL融合伴侣，一小部分融合占大多数致白血病病例。在所有国家中，超过90% MLL重排仅涉及四种融合伴侣：AFF 1、AF 9、ENL和AF 10，它们都是MLL重排的组成部分。 超延伸复合物（SEC）或组蛋白H3 K79甲基转移酶DOT 1 L的复合物。据信 这些MLL融合体通过“劫持”SEC或DOT 1 L复合物来促进MLL的表达， MLL融合的靶基因的异常激活，导致白血病的发病机制。 申请人和其他人的研究表明，ENL是SEC的化学计量组分， DOT 1 L复合物对MLL融合体的致癌功能至关重要。ENL包含一个进化的 保守的YEATS结构域。申请人发现，ENL的YEATS域用作 组蛋白乙酰化（Cell，2014，159：558-71）。重要的是，YEATS的乙酰化阅读功能 结构域对于MLL重排的白血病细胞的生长和存活是必需的（Nature，2017，543：265-269）。 这些关键的发现提供了一个概念的证据，即靶向ENL的YEATS结构域是一个潜在的 在治疗MLL重排白血病中的有价值的治疗选择。 在本FOA范围内，该提案的目标是开发ENL的有效和选择性抑制剂 YEATS域。该提案的具体目标是（1）对ENL进行高通量筛选 小分子抑制剂;（2）通过正交试验验证和评估候选命中;和（3）表征 在基于细胞的分析中的命中。从拟议的研究中获得的抑制剂将作为工具化合物， 研究ENL促进MLL融合蛋白在基因调控和疾病中的作用和机制 上维护这些化合物还将为进一步开发用于治疗癌症的小分子提供基础。 MLL易位白血病的靶向治疗。临床前研究表明，BET抑制剂表现出有限的 作为单一药剂的功效。本项目提供的选择性和有效的ENL抑制剂将是一个重要的工具 测试ENL和BET抑制剂的协同作用，为糖尿病患者提供了一种创新的治疗策略。 MLL重排白血病的治疗。