Identification of novel y-globin corepressors and advanced inhibitor development

新型 y 球蛋白辅阻遏物的鉴定和高级抑制剂的开发

• 批准号: 10400174
• 负责人: James Douglas Engel
• 金额: $ 47.16万
• 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: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400174
• 关键词: Address; Adult; Affect; Animal Model; Animals; Basic Science; Behavioral; Benign; Biochemical Genetics; Biochemistry; Biological; Biological Assay; Birth; CHD4 gene; Cardiac; Cells; Cessation of life; Chromatin; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Complex; Cooley' s anemia; Coupled; DNA Binding; DNA-Binding Proteins; Data; Development; Disease; Drug Design; Drug Targeting; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Epigenetic Process; Erythrocytes; Erythroid Progenitor Cells; Excision; Exhibits; FDA approved; Failure; Fetal Hemoglobin; Functional disorder; Generations; Genes; Genetic Transcription; Globin; Goals; Hemoglobinopathies; Human; In Vitro; Individual; Infant; Intervention; KDM1A gene; Life; Michigan; Modeling; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Oral; Papio; Pathway interactions; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Primates; Proteins; Proteomics; Regulation; Repression; Repressor Proteins; Research; Research Personnel; SMARCA5 gene; Safety; Sickle Cell Anemia; Sickle Cell Trait; Sickle Hemoglobin; Stroke; Structure; Testing; Therapeutic; Therapeutic Intervention; Tissue Model; Translations; Universities; Validation; acute chest syndrome; base; beta Globin; combinatorial; design; effective therapy; experience; fetal; follow-up; gamma Globin; gene repression; genetic corepressor; hydroxyurea; improved; in vivo; inhibitor; mortality; multiorgan damage; mutant; novel; patient subsets; polymerization; postnatal; pre-clinical; preclinical study; predictive modeling; protein complex; research study; response; side effect; structural biology; synergism; targeted treatment; tissue culture

Abstract: The ultimate goal of this research is to provide safe, effective, accessible and durable disease modification for sickle cell anemia (SCD) and β-thalassaemia (CA) that will improve multi-organ pathophysiology and reduce early death. Incontrovertible data from both basic and clinical research studies over the past 40 years support the premise that inducing fetal γ-globin (HBG) gene repression would be therapeutic in human patients. The two specific aims of this proposal focus on the manipulation and specific targeting of the transcriptional regulatory machinery that represses HBG genes during development. Our first aim is devoted to the discovery and validation of new epigenetic modifying enzymes that elicit γ-globin repressive activity in adult erythroid progenitor cells, and we describe several promising new candidate enzymes that we propose to investigate for potential drug targeting. Our second aim is to refine structure-based inhibitors of the epigenetic modifying enzyme LSD1 (KDM1a), which (we showed in a proof of concept study) could constitute an ideal target for therapeutic intervention for the treatment of these diseases. Through structure-aided design coupled to iterative enzyme inhibition and cell-based HbF induction assays, we are currently refining and testing fourth and fifth generation inhibitors (designed at the University of Michigan). These compounds have evolved to the point that they are proposed to be highly specific for LSD1 (with IC50s < 90 nM), are reversible, exhibit no behavioral or cardiac side effects and can be orally administered. We have already developed LSD1 inhibitors that were partially successful in preclinical animal studies, and here we propose to develop novel compounds with minimal undesirable on target effects. We propose to follow up these preclinical studies, in collaboration with investigators in project 2, by analysis of the effects of the best of these novel inhibitors in baboons, and if those are successful, in collaboration with project 3, in human clinical trials. The projected impact for patients suffering from β-globinopathies is that these proposed HbF-inducing therapies will be sufficiently efficacious to counter the devastating complications of these diseases such as stroke and acute chest syndrome, and with accessibility and safety parameters that will permit universal application as well as life-long use.

抽象的： 这项研究的最终目的是提供安全，有效，可及耐用的疾病修饰 镰状细胞性贫血（SCD）和β-甲性疾病（CA）将改善多器官病理生理学并减少 早期死亡。在过去40年中，基础研究和临床研究的无可争议数据支持 诱导胎儿γ-球蛋白（HBG）基因表达的前提将在人类患者中具有治疗性。 该提案的两个具体目的侧重于转录的操纵和特定靶向 反映开发过程中HBG基因的监管机制。我们的第一个目标是专门用于发现 并验证新的表观遗传修饰酶，这些酶引起γ-珠蛋白反射活性 祖细胞，我们描述了几种有前途的新候选酶，我们建议研究这些酶 潜在的药物靶向。我们的第二个目的是完善表观遗传修饰的基于结构的抑制剂 酶LSD1（KDM1A）（我们在概念验证研究中）可能构成一个理想的目标 治疗这些疾病的治疗干预措施。通过结构辅助设计耦合到 迭代酶抑制和基于细胞的HBF诱导分析，我们目前正在精炼和测试第四 和第五代抑制剂（密歇根大学设计）。这些化合物已演变为 提议它们对LSD1（IC50 <90 nm）高度具体，是可逆的，暴露于 行为或心脏副作用，可以口服。我们已经开发了LSD1抑制剂 在临床前动物研究中取得了部分成功，在这里我们建议开发新的化合物 对目标效应的最小值。我们建议在合作中跟进这些临床前研究 通过项目2的研究人员，通过分析这些新型抑制剂在狒狒中的影响，以及如果 这些在人类临床试验中与项目3合作成功。预计对患者的影响 患有β-珠蛋白质的患者是，这些提出的HBF诱导的疗法将足够有效 对抗这些疾病的毁灭性并发症，例如中风和急性胸部综合征，以及 可访问性和安全参数将允许通用应用以及终身使用。