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

基本信息

批准号：
10662232
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
项目类别：
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/10662232
关键词：
Alzheimer&apos s Disease Autophagocytosis Binding Biology Cells Chemicals Collaborations Communities Complex 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 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 drug discovery enzyme structure glutaric acidemia glycosyltransferase human disease inhibition of autophagy inhibitor multidisciplinary nanomolar programs protein degradation proteostasis sensor structural biology synergism therapeutic target

项目摘要

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.

项目概要拉撒路实验室的整体研究围绕着能量和蛋白质稳态的研究展开，因为它我们有几个跨学科的领域，涉及利用化学生物学和结构生物学研究人类疾病。围绕该主题的项目，包括研究自噬激酶和假激酶、赖氨酸的 ULK 家族在过去的 4 年里，我们使用了与糖尿病和癌症相关的代谢紊乱以及其他激酶。晶体学和化学生物学有助于开发代谢传感器 O-GlcNAc 的高效抑制剂转移酶，解决了第一个结构并鉴定了与 ULK 假激酶相关的第一个化学探针精神分裂症 ULK4，并帮助阐明赖氨酸代谢途径中酶的第一个结构 DHTKD1。我们未来五年的目标包括进一步了解 ULK 激酶家族。 ULK1 和 ULK2 是自噬途径（一种保守的代谢途径）的主要起始酶因此，在饥饿期间，细胞成分会被降解，以用于质量控制和能量产生。该通路被认为对从癌症到阿尔茨海默氏病等疾病至关重要，但仍然存在当我们以不同的方式抑制自噬时，细胞会发生什么？使用选择性探针在不同疾病模型中的通路阶段有何作用？家族成员 ULK4，它没有催化活性，但以纳摩尔效力结合 ATP，并且可能具有 ATP 结合的另一个主要目标涉及赖氨酸代谢途径，其中有几个先天性的。发现代谢错误。该途径中的酶如何发挥作用，并且可以抑制其他途径。该途径中的酶可以阻止戊二酸尿症患者中产生的中间体的毒性累积？该研究计划的总体愿景是开发化学探针并获得高分辨率晶体结构，以更好地了解这些代谢途径中的关键酶并确定它们是否在西奈山研究界的背景下，我们正在研究人类疾病的治疗目标。能够与我们的同事合作，利用我们在化学和结构生物学方面的优势提供与我们同事在人类生物学或医学方面的专业知识相协同的分子理解化学，例如我们与药物发现研究所的总体合作以及我们与涉及癌症、遗传疾病、糖尿病和神经退行性疾病，随着新机遇的出现，我们可以做到。提供我们在糖基转移酶、激酶和假激酶分子基础方面的专业知识，以及蛋白质降解途径来开发由 MIRA 资金支持的新项目，同时仍然关注上述核心项目。