Chemical and Structural Approaches to Study Energy Homeostasis Pathways in Cancer and Metabolic disorders

研究癌症和代谢紊乱能量稳态途径的化学和结构方法

• 批准号: 10405224
• 负责人: Michael Block Lazarus
• 金额: $ 46.45万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405224
• 关键词: Alzheimer' s Disease; Autophagocytosis; Binding; Biology; Cells; Chemicals; Collaborations; Communities; Complex; Crystallization; Crystallography; Degradation Pathway; Diabetes Mellitus; Disease; Disease model; Enzymes; Family; Family member; Funding; Generations; Genetic Diseases; Goals; Homeostasis; Human Biology; Human Pathology; Inborn Errors of Metabolism; Institutes; Link; Lysine; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolic Pathway; Molecular; Nerve Degeneration; O-GlcNAc transferase; Pathway interactions; Patients; Pharmaceutical Chemistry; Phosphotransferases; Positioning Attribute; Quality Control; Research; Resolution; Role; Schizophrenia; Starvation; Structure; Vision; cancer genetics; diabetes mellitus genetics; drug discovery; enzyme structure; glutaric acidemia; glycosyltransferase; human disease; inhibitor; multidisciplinary; nanomolar; programs; protein degradation; proteostasis; sensor; structural biology; therapeutic target

Project Summary The overall research in the Lazarus Lab revolves around studying energy and protein homeostasis as it relates to human disease using chemical biology and structural biology. We have several multidisciplinary projects around this topic, including studying the ULK family of autophagy kinases and pseudokinases, lysine metabolism disorders, and other kinases related to diabetes and cancer. Over the last 4 years, we have used crystallography and chemical biology to help develop highly potent inhibitors of the metabolic sensor O-GlcNAc transferase, solved the first structures and identify the first chemical probes of the ULK pseudokinase linked to schizophrenia ULK4, and helped elucidate the first structure of an enzyme in the lysine metabolic pathway DHTKD1. Our goals over the next five-year period include further understanding of the ULK family of kinases. ULK1 and ULK2 are the main initiating enzymes for the autophagy pathway, a conserved metabolic pathway whereby cellular components get degraded for quality control and energy generation during starvation. The pathway is thought to be critical in diseases ranging from cancer to Alzheimer’s disease, yet there are still major gaps in our understanding of the pathway. What happens to cells when you inhibit autophagy at different stages of the pathway in different disease models using selective probes? What is the role of the mysterious family member ULK4, which has no catalytic activity but binds ATP with nanomolar potency and likely has a function for the ATP binding. Another major goal involves the lysine metabolic pathway, in which several inborn errors of metabolism are found. How do the enzymes in this pathway function, and can inhibiting other enzymes in this pathway block the toxic buildup of intermediates that arise in glutaric aciduria patients? The overall vision of the research program is to develop chemical probes and obtain high-resolution crystal structures to better understand key enzymes in these metabolic pathways and determine if they are therapeutic targets for human diseases. Within the context of the Mount Sinai research community, we are well-positioned to collaborate with our colleagues to leverage our strength in chemical and structural biology to provide molecular understanding that synergizes with our colleagues’ expertise in human biology or medicinal chemistry, like our overarching collaboration with the Drug Discovery Institute here and our collaborations that involve cancer, genetic diseases, diabetes, and neurodegeneration. As new opportunities arise, we can provide our expertise in the molecular underpinnings of glycosyltransferases, kinases and pseudokinases, and protein degradation pathways to develop new projects supported by the MIRA funding, while still focusing on the core projects described above.

项目摘要 拉撒路实验室的总体研究围绕着研究能量和蛋白质稳态的研究 使用化学生物学和结构生物学涉及人类疾病。我们有几个多学科 围绕该主题的项目，包括研究自噬激酶和伪动酶的ULK家族，赖氨酸 代谢疾病以及与糖尿病和癌症有关的其他激酶。在过去的四年中，我们使用了 晶体学和化学生物学，以帮助开发代谢传感器O-GLCNAC的高效抑制剂 转移酶，解决了第一个结构，并确定了与ULK假酶的第一个化学问题 精神分裂症ULK4，并帮助阐明了赖氨酸代谢途径中酶的第一个结构 DHTKD1。 我们在接下来的五年中的目标包括进一步了解ULK激酶家族。 ULK1和ULK2是自噬途径的主要启动酶，这是一种配置的代谢途径 因此，在饥饿期间，细胞成分会降解以控制质量控制和能量。 人们认为途径对于从癌症到阿尔茨海默氏病的疾病至关重要，但仍有 我们对路径的理解的主要差距。当您抑制不同的自噬时，细胞会发生什么 使用选择性问题的不同疾病模型中的途径阶段？神秘的角色是什么 家庭成员ULK4，没有催化活性，但与纳摩尔效力结合，可能具有 ATP结合的功能。另一个主要目标涉及赖氨酸代谢途径，其中有几个天生 发现新陈代谢的错误。该途径中的酶如何抑制其他 该途径中的酶阻止了谷氨酸酸尿症患者出现的中间体的有毒积聚？ 研究计划的总体愿景是发展化学问题并获得高分辨率 晶体结构可以更好地理解这些代谢途径中的关键酶，并确定它们是否是 人类疾病的治疗靶标。在西奈山研究社区的背景下，我们是 位置良好，可以与我们的同事合作，以利用我们在化学和结构生物学方面的力量 提供分子理解，该理解与我们的同事在人类生物学或医学方面的专业知识协同作用 化学，就像我们在这里与药物发现研究所的总体合作以及我们的合作 吞噬癌症，遗传疾病，糖尿病和神经退行性。随着新机会的出现，我们可以 提供我们在糖基转移酶，激酶和伪运动酶的分子基础上提供的专业知识，以及 蛋白质降解途径开发由MIRA资金支持的新项目，同时仍关注 上述核心项目。