Development of ASH1L inhibitors for acute leukemia

治疗急性白血病的ASH1L抑制剂的开发

• 批准号: 10523103
• 负责人: Jolanta Grembecka
• 金额: $ 56.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523103
• 关键词: ASH1L gene; Acute Myelocytic Leukemia; Acute T Cell Leukemia; Acute leukemia; Affinity; Binding; Cells; Cessation of life; Characteristics; Chemicals; Clinical Trials; Complex; Data; Defect; Development; Diagnosis; Disease; Down-Regulation; Drug Kinetics; Exhibits; Failure; Gene Expression; Genes; Goals; Growth; HOXA9 gene; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Histones; Homeobox Genes; In Vitro; Lead; Leukemic Cell; Lysine; MEIS1 gene; MLL gene; Malignant Neoplasms; Metabolic; Methylation; MicroRNAs; Mixed-Lineage Leukemia; Modeling; Mus; Mutation; Outcome; Outcome Study; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Play; Prognosis; Proliferating; Property; Proteins; Refractory Disease; Regulation; Reporting; Research; Role; SET Domain; Sampling; Solubility; Specificity; Structure; Survival Rate; T-Cell Development; Therapeutic; Therapeutic Agents; Toxic effect; United States; Up-Regulation; Work; acute leukemia cell; antileukemic agent; chemotherapy; cofactor; design; effectiveness evaluation; efficacy study; hematopoietic differentiation; histone methyltransferase; improved; in vitro activity; in vivo; inhibitor; innovation; knock-down; lead candidate; leukemia; leukemogenesis; loss of function mutation; mouse model; nanomolar; novel; novel therapeutic intervention; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; screening; small molecule; small molecule inhibitor; targeted agent; tool; treatment strategy

Acute leukemia is a group of diseases associated with various genetic alterations that block differentiation and increase proliferation of hematopoietic progenitor cells. Acute Myeloid Leukemia (AML) patients have very poor prognosis with currently available treatments, reflected by a 5-year survival rate of only 27%. Dysregulation of HOX genes is associated with numerous malignancies, including acute leukemias. In AML high level of HOX genes, in particular HOXA9, is associated with refractory disease and very poor prognosis, emphasizing the urgent need for novel therapies. Therefore, small molecules that reduce HOX genes expression might represent a novel promising treatment strategy for acute leukemia patients. ASH1L (Absent, small or homeotic 1-like) is a histone methyltransferase, which belongs to the Trithorax group of proteins regulating HOX genes expression. ASH1L knockdown studies have demonstrated a critical role of ASH1L in development of leukemia's with translocations of the MLL gene through regulation of HOXA9 and MEIS1 expression. Our own studies have validated that the SET domain of ASH1L plays a critical role in leukemogenesis, both in the context of MLL- rearranged leukemias and other high HOXA leukemias. Importantly, Ash1l-deficient mice exhibit no overt hematopoietic failure in the steady-state conditions. Based on all these findings we believe that the ASH1L SET domain represents a valid target in acute leukemias with high HOXA expression. In this project, we propose to develop small molecule inhibitors of ASH1L histone methyltransferase as a potential therapeutic strategy for acute leukemias with high HOXA expression. To this end, we identified very promising class of small molecules that bind to the SET domain of ASH1L and inhibit its enzymatic activity and substantially optimized their potency, resulting in compounds with nanomolar binding affinities and high selectivity to ASH1L These compounds inhibit proliferation, induce differentiation and downregulate expression of HOXA genes in MLL leukemia cells, demonstrating highly specific mode of action. In this project we will optimize ASH1L inhibitors to further improve their potency and drug-like properties with the goal to develop compounds suitable for in vivo efficacy studies in AML models. In Aim 1 we will employ medicinal chemistry to improve potency and drug-like properties, including metabolic stability, cellular permeability and solubility, of the lead compounds we already identified. In Aim 2 we will carry out extensive characterization of ASH1L inhibitors in a panel of acute leukemia cells with high and low level of HOXA genes expression to assess their potency, mechanism of action and specificity. Aim 3 will be devoted to assess the in vivo efficacy of ASH1L inhibitors in disseminated models of acute leukemia. We expect the outcome of these studies will result in very potent and selective ASH1L inhibitors that might provide novel therapeutic approach for acute leukemias.

急性白血病是一组与各种遗传改变相关的疾病，这些疾病会阻断分化和 增加造血祖细胞的增殖。急性髓细胞性白血病（AML）患者非常差 当前可用治疗的预后，仅5年生存率仅为27％。失调的 HOX基因与包括急性白血病在内的许多恶性肿瘤有关。在AML高水平的HOX中 基因，特别是Hoxa9，与难治性疾病和预后非常差有关，强调了 迫切需要新型疗法。因此，降低HOX基因表达的小分子可能代表 急性白血病患者的一种新型有希望的治疗策略。 ASH1L（缺少，小或类似于1类）是 组蛋白甲基转移酶属于调节HOX基因表达的蛋白质蛋白。 ASH1L敲低研究表明，ASH1L在白血病的发展中起着关键作用 通过调节HOXA9和MEIS1表达，MLL基因的易位。我们自己的研究有 在MLL的背景下 重新排列的白血病和其他高HOXA白血病。重要的是，ASH1L缺陷小鼠没有明显的 在稳态条件下的造血衰竭。基于所有这些发现，我们认为ASH1L设置 域代表具有高HOXA表达的急性白血病的有效靶标。 在这个项目中，我们建议开发ASH1L组蛋白甲基转移酶的小分子抑制剂 具有高HOXA表达的急性白血病的潜在治疗策略。为此，我们确定了 有希望的小分子与ASH1L的固定结构域结合并抑制其酶活性和 实质上优化了它们的效力，从而产生了具有纳摩尔结合亲和力的化合物 对ASH1L的选择性这些化合物抑制增殖，诱导分化和下调表达 MLL白血病细胞中的Hoxa基因，表现出高度特异性的作用方式。在这个项目中，我们将 优化ASH1L抑制剂，以进一步提高其效力和类似毒品的特性，以开发 适用于AML模型中的体内功效研究的化合物。在AIM 1中，我们将采用药物化学来 提高效力和类似药物的特性，包括代谢稳定性，细胞渗透性和溶解度 我们已经确定的铅化合物。在AIM 2中，我们将进行ASH1L抑制剂的广泛表征 在急性白血病细胞中，HOXA基因表达高水平和低水平以评估其效力， 作用和特异性机理。 AIM 3将专门评估ASH1L抑制剂在体内功效 急性白血病的传播模型。我们预计这些研究的结果将导致非常有效，并且 选择性的ASH1L抑制剂可能会为急性白血病提供新颖的治疗方法。