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.

抽象的 组蛋白的表观遗传修饰在调节转录和失调中发挥关键作用 表观遗传机制已成为癌症发生和进展的重要驱动因素。组蛋白 赖氨酸甲基化是重要的表观遗传标记，受组蛋白甲基转移酶动态调控 “作家”和组蛋白赖氨酸去甲基化酶“橡皮擦”（KDM）。 KDM 在结构上包括两个 机械上不同类别的酶，并且有确凿的证据表明较大的 Jumonji C 中的 KDM4B (JmjC) 类在多种癌症中具有特别关键的作用，包括乳腺癌和前列腺癌、急性髓系癌症 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： KDM4B 在乳腺癌和神经母细胞瘤中的作用。这些结果促使我们开始筛选、细胞 生物学和结构生物学致力于鉴定 KDM4B 的特异性抑制剂。我们研究的两个重要发现 提供概念证明，证明靶向 KDM4B 是一种潜在有价值的癌症治疗选择 治疗。首先，N-Myc 招募 KDM4B 以在 Myc 结合处维持低水平的抑制性 H3K9me2/me3 位点并促进神经母细胞瘤生长。其次，小分子环吡酮抑制KDM4B活性， 抑制 N-Myc 通路并减少神经母细胞瘤的生长。 该提案在 FOA 范围内的直接目标是开发新颖且有效的 KDM4B 抑制剂，在 JmjC 类 KDM 中表现出特异性。此类抑制剂可用于 开发有效的体内化学探针来研究 KDM4B 和 KDM 家族其他成员的作用 在相关的临床前癌症模型中。长期目标是开发小分子癌症疗法 目标 KDM4B。先前的生化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，当我们 继续。四个具有不同专业知识的实验室已经并将继续在该项目上进行合作：君 Yang 和 Andrew Davidoff（命中验证）、Taosheng Chen 博士（筛选）和 Stephen White 博士 （生物物理学研究和结构生物学）。此外，Zoran Rankovic 博士将提供药物化学课程 随着我们迈向治疗开发，专业知识将变得越来越重要。定义如下 FOA，该项目包括 3 个阶段：检测开发（阶段 1）、初级筛选实施（阶段 2) 并点击验证（第 3 阶段）。第 1 阶段和第 2 阶段已经进行得很顺利，因此重点将放在阶段上 3.