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: 10529302
• 负责人: Hong Wen
• 金额: $ 43.15万
• 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/10529302
• 关键词: Acetylation; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adult; Automation; Binding; Biochemical; Biological Assay; Biophysics; Bromodomains and extra-terminal domain inhibitor; 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; Prognosis; Proliferating; Reader; Reading; Series; Structure; Testing; Therapeutic; Titrations; Triage; Validation; cytotoxicity test; disorder subtype; driver mutation; drug development; effective therapy; gene translocation; genome-wide; high throughput screening; histone methyltransferase; in vivo; inhibitor; innovation; leukemia; pharmacologic; 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.

项目概要 混合谱系白血病 (MLL) 基因重排约占婴儿急性白血病的 80% 淋巴细胞白血病 (ALL) 和 35-50% 的婴儿急性髓细胞白血病 (AML)。患者轴承 MLL 基因的重排与不良预后有关，尤其是对药物的反应较差。 标准治疗。目前仍然缺乏针对这种致命疾病亚型的有效疗法。 从分子角度来说，MLL 的染色体间易位导致 MLL 的 N 末端与 各种融合伙伴的C末端，被称为疾病的“驱动”病变。其中还有更多 超过 70 个 MLL 融合伙伴，一小部分融合导致​​了大多数白血病病例。总共超过 90% MLL 重排仅涉及 4 个融合伙伴：AFF1、AF9、ENL 和 AF10，它们都是 超延伸复合物 (SEC) 或组蛋白 H3K79 甲基转移酶 DOT1L 的复合物。据信 这些MLL融合通过“劫持”SEC或DOT1L复合体共享一个共同的途径来促进 MLL 融合靶基因的异常激活，导致白血病的发病机制。 申请人和其他人的研究表明，ENL（SEC 的化学计量成分）和 DOT1L 复合物对于 MLL 融合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 域充当以下内容的阅读器： 组蛋白乙酰化（Cell，2014，159：558-71）。重要的是，YEATS 的乙酰化读取功能 结构域对于 MLL 重排的白血病细胞的生长和存活至关重要 (Nature, 2017, 543:265-269)。 这些关键发现提供了概念证明，即针对 ENL 的 YEATS 域是一种潜在的方法。 治疗 MLL 重排白血病的有价值的治疗选择。 该提案在 FOA 范围内的目标是开发有效且选择性的 ENL 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) 通过正交测定验证和评估候选命中； (3) 表征 基于细胞的测定中的命中。从拟议的研究中获得的抑制剂将作为工具化合物 研究ENL在促进MLL融合蛋白在基因调控和疾病中的功能和机制 维护。这些化合物也将为进一步开发小分子药物提供基础 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 作为单一药物的功效。该项目提供的选择性强效ENL抑制剂将成为一个重要的工具 测试 ENL 和 BET 抑制的协同作用，为该病提供创新的治疗策略 治疗 MLL 重排白血病。