Identification of novel y-globin corepressors and advanced inhibitor development

摘要： 这项研究的最终目标是提供安全、有效、可获得和持久的疾病治疗 镰状细胞性贫血(SCD)和β-地中海贫血(CA)，将改善多器官病理生理学，减少 早逝。过去40年来自基础和临床研究的无可争辩的数据支持 诱导胎儿γ-珠蛋白(HbG)基因抑制的前提是对人类患者具有治疗作用。这个 这项建议的两个具体目标集中在对转录的操纵和特定靶向 在发育过程中抑制HBG基因的调控机制。我们的第一个目标是致力于这一发现 并验证了诱导成人红系γ珠蛋白抑制活性的新的表观遗传修饰酶 前体细胞，我们描述了几种有希望的新的候选酶，我们建议研究它们 潜在的药物靶向。我们的第二个目标是提纯表观遗传修饰的基于结构的抑制物 酶LSD1(KDM1A)，它(我们在概念研究的证明中显示)可以构成理想的靶标 对这些疾病的治疗的治疗干预。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，我们目前正在提炼和测试第四个 和第五代抑制剂(由密歇根大学设计)。这些化合物已经进化成 指出它们被提议高度针对LSD1(具有IC50和90 nm)，是可逆的，证明号 行为或心脏副作用，可口服。我们已经开发出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 将对目标的影响降至最低。我们建议合作跟进这些临床前研究。 与项目2中的研究人员一起，通过分析这些最好的新型抑制剂对狒狒的影响，以及如果 与项目3合作，这些项目在人体临床试验中取得了成功。预计对患者的影响 患有β球蛋白病的是，这些建议的HBF诱导疗法将足以有效地 对抗这些疾病的破坏性并发症，如中风和急性胸腔综合征，并与 可获得性和安全参数，将允许普遍使用和终身使用。

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.