Development of small molecules to target KDM4B

开发针对 KDM4B 的小分子

• 批准号: 9580417
• 负责人: Taosheng Chen
• 金额: $ 41.06万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9580417
• 关键词: Acute Myelocytic Leukemia; Binding Sites; Biochemical; Biological; Biological Assay; Biological Process; Biological Sciences; Biology; Biophysics; Breast Cancer Cell; Calorimetry; Cancer Model; Catalytic Domain; Cell Cycle Progression; Cells; Cellular biology; Chemicals; Clinical Trials; Collection; Development; Disease; Disease model; Dose; Drug Kinetics; Ensure; Enzymes; Epigenetic Process; Estrogen Receptor alpha; Family; Family member; Fluorescence Resonance Energy Transfer; Fusion Oncogene Proteins; Future; Gene Expression; Genetic Transcription; Goals; Growth; Histones; Hypoxia; Image; Immunofluorescence Immunologic; In Vitro; Institution; Laboratories; Lead; Libraries; Lysine; MLL-AF9; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Methylation; Molecular; Neoplasm Metastasis; Neuroblastoma; Oncogenic; Oncoproteins; Pathogenicity; Pathway interactions; Pharmaceutical Chemistry; Phenotype; Play; Pre-Clinical Model; Protein Isoforms; Proteins; Publishing; Research Personnel; Resource Sharing; Resources; Role; Saint Jude Children' s Research Hospital; Specificity; Stem cells; Structure; Substrate Specificity; Support Groups; Surface Plasmon Resonance; Testing; Therapeutic; Time; Titrations; Translating; Treatment Efficacy; Validation; X-Ray Crystallography; Yang; Zoran; assay development; base; biophysical analysis; cancer cell; cancer initiation; cancer therapy; cheminformatics; drug discovery; genome integrity; group support; high throughput screening; histone demethylase; histone methyltransferase; histone modification; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; malignant breast neoplasm; member; novel; pre-clinical; programs; recruit; response; screening; small molecule; structural biology; targeted cancer therapy; therapeutic development; therapeutic target; tool; transcription factor; tumor progression; tumorigenesis

ABSTRACT Epigenetic modifications of histone proteins play key roles in regulating transcription, and dysregulation of the epigenetic machinery has emerged as important driver of cancer initiation and progression. Histone lysine methylation is an important epigenetic mark that is dynamically regulated by histone methyltransferase `writers' and histone lysine demethylase `erasers' (KDMs). The KDMs comprise two structurally and mechanistically distinct classes of enzymes, and there is firm evidence that KDM4B in the larger Jumonji C (JmjC) class has a particularly key role in several cancers including breast and prostate cancer, acute myeloid leukemia and neuroblastoma. Published and ongoing studies from our group support the importance of KDM4B in breast cancer and neuroblastoma. These results have prompted us to initiate screening, cell biology and structural biology efforts to identify specific inhibitors of KDM4B. Two key findings from our studies provide a proof-of-concept that targeting KDM4B is a potentially valuable therapeutic option in cancer treatment. First, N-Myc recruits KDM4B to maintain low levels of repressive H3K9me2/me3 at Myc-binding sites and promotes neuroblastoma growth. Second, the small molecule ciclopirox inhibits KDM4B activity, suppresses the N-Myc pathway and reduces neuroblastoma growth. The immediate goal of this proposal within the scope of this FOA is to develop novel and potent inhibitors of KDM4B that display specificity within the JmjC class of KDMs. Such inhibitors can then be used to develop competent in vivo chemical probes to study the roles of KDM4B and other members of the KDM family in relevant preclinical cancer models. A longer term goal is to develop small molecule cancer therapies that target KDM4B. Previous biochemical and structural biology studies have thoroughly characterized the catalytic mechanism and substrate specificities of these enzymes, and this information will fully exploited as we proceed. Four laboratories with diverse expertise have and will continue to collaborate on this project: Drs. Jun Yang and Andrew Davidoff (hit validation), Dr. Taosheng Chen (screening), and Dr. Stephen White (biophysical studies and structural biology). In addition, Dr. Zoran Rankovic will provide medicinal chemistry expertise that will be increasingly important as we move towards therapeutic development. As defined within the FOA, the project includes 3 stages: assay development (Stage 1), primary screen implementation (Stage 2) and hit validation (Stage 3). Stages 1 and 2 are well advanced and the emphasis will therefore be on Stage 3.

摘要 组蛋白的表观遗传修饰在调节转录和失调中起关键作用 表观遗传机制已经成为癌症发生和发展的重要驱动力。组蛋白 赖氨酸甲基化是一种重要的表观遗传标记，受组蛋白甲基转移酶的动态调节 “写入器”和组蛋白赖氨酸脱甲基酶“擦除器”（KDM）。KDM在结构上包括两个， 机械上不同类别的酶，有确凿的证据表明，KDM 4 B在较大的Jumonji C （JmjC）类在包括乳腺癌和前列腺癌、急性骨髓性白血病和骨髓性白血病在内的几种癌症中具有特别关键的作用。 白血病和神经母细胞瘤。我们小组已发表和正在进行的研究支持以下重要性： 乳腺癌和神经母细胞瘤中的KDM 4 B。这些结果促使我们开始筛选，细胞 生物学和结构生物学的努力，以确定KDM 4 B的特异性抑制剂。我们研究的两个关键发现 提供了一个概念验证，靶向KDM 4 B是一种潜在的有价值的癌症治疗选择 治疗首先，N-Myc募集KDM 4 B以在Myc结合时维持低水平的抑制性H3 K9 me 2/me 3。 并促进神经母细胞瘤的生长。其次，小分子环吡酮抑制KDM 4 B活性， 抑制N-Myc通路并减少神经母细胞瘤生长。 在本FOA范围内，该提案的直接目标是开发新颖而有效的 KDM 4 B的抑制剂，其在KDM的JmjC类内显示特异性。这样的抑制剂然后可以用于 开发合适的体内化学探针，以研究KDM 4 B和KDM家族其他成员的作用 在相关的临床前癌症模型中。更长期的目标是开发小分子癌症疗法， 目标是KDM 4 B以前的生物化学和结构生物学研究已经彻底表征了催化 这些酶的机制和底物特异性，这些信息将充分利用，因为我们 继续.四个拥有不同专业知识的实验室已经并将继续在这个项目上合作： Yang和Andrew Davison（命中验证）、Dr. Taosheng Chen（筛选）和Dr. Stephen白色 （生物物理学和结构生物学）。此外，佐兰·兰科维奇博士将提供药物化学 随着我们向治疗发展，这些专业知识将变得越来越重要。内定义的 根据FOA，该项目包括3个阶段：检测开发（第1阶段）、初步筛选实施（第 2)和命中验证（阶段3）。第一阶段和第二阶段已经很深入，因此重点将放在第二阶段 3.