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基因改变有关的疾病，这些改变阻碍了分化和 促进造血祖细胞增殖。急性髓系白血病(AML)患者非常差 目前可用的治疗方法对预后的影响，反映在5年存活率仅为27%。失调症 HOX基因与许多恶性肿瘤有关，包括急性白血病。急性髓系白血病中高水平的HOX 基因，特别是HOXA9，与难治性疾病和非常糟糕的预后有关，强调了 迫切需要新的治疗方法。因此，降低HOX基因表达的小分子可能代表 一种新的有希望的急性白血病患者的治疗策略。Ash1(缺失的、小的或类似同源的1)是一种 组蛋白甲基转移酶，属于三胸蛋白家族，调节HOX基因的表达。 Ash1基因敲除研究表明，Ash1基因在白血病的发生和发展中起着关键作用。 通过HOXA9和Meis1的表达调控MLL基因的易位。我们自己的研究已经 证实了Ash11的SET结构域在白血病发生中起着关键作用，无论是在MLL- 重排白血病和其他高Hoxa白血病。重要的是，缺乏Ash1基因的小鼠没有表现出明显的 稳态条件下的造血功能衰竭。基于所有这些发现，我们认为阿什尔人 结构域是HoxA高表达的急性白血病的有效靶点。 在本项目中，我们建议开发组蛋白甲基转移酶的小分子抑制剂作为 Hoxa高表达的急性白血病的潜在治疗策略。为此，我们确定了非常 一类很有前途的小分子，它与Ash1的设定结构域结合并抑制其酶活性和 大大优化了它们的效力，产生了具有纳摩尔结合亲和力和高 这些化合物抑制增殖、诱导分化和下调表达 HoxA基因在MLL白血病细胞中的表达，显示出高度特异性的作用模式。在这个项目中，我们将 优化Ash1抑制剂，进一步提高其效力和类药物性能，目标是开发 适合急性髓系白血病模型体内疗效研究的化合物。在目标1中，我们将使用药物化学来 改善药物效力和类药物特性，包括代谢稳定性、细胞渗透性和溶解性 我们已经确定了先导化合物。在目标2中，我们将对Ash1抑制剂进行广泛的表征 在一组HoxA基因高水平和低水平表达的急性白血病细胞中，评估它们的效力， 作用机制和特异性。Aim 3将致力于评估Ash1抑制剂在体内的疗效 急性白血病的播散性模型。我们预计这些研究的结果将产生非常有力的和 选择性Ash1抑制剂，可能为急性白血病提供新的治疗方法。