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: 10769149
• 负责人: Michael Block Lazarus
• 金额: $ 12.25万
• 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/10769149
• 关键词: Alzheimer' 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

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 拉撒路实验室的整体研究围绕着研究能量和蛋白质的体内平衡， 涉及利用化学生物学和结构生物学的人类疾病。我们有几个多学科的 围绕这一主题的项目，包括研究ULK家族的自噬激酶和假激酶，赖氨酸 代谢紊乱和其他与糖尿病和癌症相关的激酶。在过去的四年里，我们使用 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假激酶连接的第一个化学探针。 精神分裂症ULK 4，并帮助阐明了赖氨酸代谢途径中酶的第一个结构 DHTKD 1. 我们未来五年的目标包括进一步了解ULK激酶家族。 ULK 1和ULK 2是自噬途径（一种保守的代谢途径）的主要起始酶 由此细胞成分在饥饿期间为了质量控制和能量产生而退化。的 这条通路被认为在从癌症到阿尔茨海默病的疾病中至关重要，但仍然存在 我们对这条道路的理解存在重大差距。当你在不同的温度下抑制自噬时， 阶段的途径在不同的疾病模型使用选择性探针？神秘的角色是什么 家族成员ULK 4，它没有催化活性，但以纳摩尔效力结合ATP， ATP结合的功能。另一个主要目标涉及赖氨酸代谢途径，其中几个先天性 代谢的错误被发现。在这个途径中的酶是如何发挥作用的，以及抑制其他的酶是如何发挥作用的？ 这种途径中的酶阻断了谷氨酸尿症患者中出现的中间产物的毒性积累？ 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 人类疾病的治疗目标。在西奈山研究社区的背景下，我们是 我们有能力与我们的同事合作，利用我们在化学和结构生物学方面的优势， 提供分子理解，与我们同事在人类生物学或医学方面的专业知识协同作用 化学，比如我们与这里的药物发现研究所的全面合作， 包括癌症、遗传疾病、糖尿病和神经退化。随着新机遇的出现，我们可以 提供我们在糖基转移酶、激酶和假激酶的分子基础方面的专业知识， 蛋白质降解途径，以开发由MIRA资助的新项目，同时仍然专注于 上述核心项目。

项目成果

Selective Inhibitors of Autophagy Reveal New Link between the Cell Cycle and Autophagy and Lead to Discovery of Novel Synergistic Drug Combinations.

自噬的选择性抑制剂揭示了细胞周期与自噬之间的新联系，并导致发现了新型协同药物组合。

• DOI: 10.1021/acschembio.2c00710
• 发表时间: 2022-12-16
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Sung, Kisa;Kurowski, Agata;Lansiquot, Carisse;Wan, Kanny K.;Patnaik, Samarjit;Walsh, Martin J.;Lazarus, Michael B.
• 通讯作者: Lazarus, Michael B.

Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors.

• DOI: 10.1021/jacs.8b07328
• 发表时间: 2018-10-24
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Martin SES;Tan ZW;Itkonen HM;Duveau DY;Paulo JA;Janetzko J;Boutz PL;Törk L;Moss FA;Thomas CJ;Gygi SP;Lazarus MB;Walker S
• 通讯作者: Walker S