Development of ASH1L inhibitors for acute leukemia

治疗急性白血病的ASH1L抑制剂的开发

基本信息

批准号：
10303031
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
项目类别：
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/10303031
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 Crystallization 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 MicroRNAs Mixed-Lineage Leukemia Modeling Mus Mutation Outcome Outcome Study Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Play Prognosis 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 base 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

项目摘要

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相关的疾病，这些基因改变阻碍分化和分化增加造血祖细胞的增殖。急性髓系白血病（AML）患者的病情非常糟糕目前可用治疗的预后较差，5 年生存率仅为 27%。失调 HOX 基因与许多恶性肿瘤相关，包括急性白血病。 AML 中 HOX 水平高基因，特别是 HOXA9，与难治性疾病和极差的预后相关，强调迫切需要新的疗法。因此，减少 HOX 基因表达的小分子可能代表一种针对急性白血病患者的新的有前景的治疗策略。 ASH1L（不存在、小或同源异型 1 样）是组蛋白甲基转移酶，属于调节 HOX 基因表达的 Trithorax 蛋白组。 ASH1L 敲低研究表明 ASH1L 在白血病发展中发挥着关键作用通过调节 HOXA9 和 MEIS1 表达来实现 MLL 基因的易位。我们自己的研究有证实 ASH1L 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，Ash1l 缺陷小鼠没有表现出明显的稳态条件下的造血衰竭。基于所有这些发现，我们相信 ASH1L SET 结构域代表了具有高 HOXA 表达的急性白血病的有效靶点。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 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有前景的小分子，可与 ASH1L 的 SET 结构域结合并抑制其酶活性，显着优化了它们的效力，产生了具有纳摩尔结合亲和力和高结合力的化合物对 ASH1L 的选择性这些化合物抑制增殖、诱导分化并下调表达 MLL 白血病细胞中 HOXA 基因的变化，展示了高度特异性的作用模式。在这个项目中我们将优化 ASH1L 抑制剂，进一步提高其效力和类药特性，目标是开发适合用于 AML 模型体内功效研究的化合物。在目标 1 中，我们将利用药物化学来提高效力和药物样特性，包括代谢稳定性、细胞通透性和溶解度我们已经鉴定出先导化合物。在目标 2 中，我们将对 ASH1L 抑制剂进行广泛的表征在一组具有高水平和低水平 HOXA 基因表达的急性白血病细胞中评估其效力，作用机制和特异性。目标 3 将致力于评估 ASH1L 抑制剂在急性白血病播散模型。我们预计这些研究的结果将产生非常有效和选择性 ASH1L 抑制剂可能为急性白血病提供新的治疗方法。