Target-based Assays and Screening Strategies for Chemical Probe and Therapeutic Lead Discovery

化学探针和治疗性先导化合物发现的基于靶标的测定和筛选策略

• 批准号: 9551433
• 负责人: James Inglese
• 金额: $ 36.66万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9551433
• 关键词: Agonist; Antibiotics; Antineoplastic Agents; Applications Grants; Biochemical; Biological Assay; Brain natriuretic peptide; CD47 gene; Cell Proliferation; Chemicals; Collaborations; Complement; Complex; Cyclic AMP; Development; Disease; Drug Targeting; Enzyme Inhibitor Drugs; Enzymes; Evaluation; Extramural Activities; Goals; Guanylate Cyclase; Hormones; Laboratories; Lead; Ligand Binding; Ligands; Link; Mediating; Messenger RNA; Molecular Target; National Institute of Child Health and Human Development; National Institute of Dental and Craniofacial Research; Natural Products; Nerve; Normal tissue morphology; Nucleic Acids; PTPNS1 gene; Peripheral; Pharmacological Treatment; Pharmacology; Physiology; Proteins; Pruritus; Quality of life; RNA; Radiation therapy; Regulator Genes; Research; Science; Scientist; Second Messenger Systems; Spinal Cord; System; Technology; Testing; Therapeutic; Transferase; Translations; United States National Institutes of Health; Untranslated RNA; Work; assay development; atrial natriuretic factor receptor B; base; cell type; chronic itch; design; drug discovery; high throughput screening; method development; novel; palmitoylation; programs; protein protein interaction; prototype; radixin protein; receptor; research and development; scaffold; screening; small molecule; small molecule libraries; transmission process; tumor

This project includes the development of biochemical and target-focused assays based on specific protein or nucleic acid targets implicated in disease. The assay designs are considered in the context of analysis and progression strategies for evaluation of a wide range of compound classes using high throughput screening technologies. There is a strong emphasis on methods development research to advance assay and lead discovery efficiency. Complementing these activities we also explore and devise approaches for the interrogation of complex chemical libraries (e.g., natural product extracts, mRNA display). The work from this program is used to support a range of grant applications and prototype projects. The following are on-going: Radixin-mediated assembly of cAMP effectors. cAMP is a universal second messenger used by several hormones in every cell type. It is involved in multiple aspects of normal physiology and disease and thus a valid though challenging target for drug discovery. In collaboration with D. Altschuler (U. Pittsburgh) we are investigating assay strategies to specifically target a cAMP effector-scaffold complex involved in cAMP-dependent cell proliferation. Targeting protein palmitoylation with small molecules. In collaboration with A. Banerjee (NICHD, NIH) we are developing 1536-well compatible protein palmitoyl acyl transferase assays to evaluate chemical libraries for potential inhibitors of the enzyme as possible therapeutic leads for the large number of diseases to which this class of enzyme have been linked. These compounds are also anticipated to have value as structural, functional and pharmacological probes. Strategies for the discovery of small molecule ligands of RNA. In collaboration with Prof. N. Baird (U. Sciences) we are exploring assay designs to probe the interaction of small molecules with non-coding gene-regulatory mRNAs. The research has the potential of the discovery of novel antibiotics or anticancer agents. Assay development to enable discovery of novel small molecule antagonists of the receptor guanylate cyclase Npr1. In collaboration with M. Hoon (NIDCR, NIH) we are developing and testing novel assays of the b-type natriuretic peptide (BNP) receptor, Npr1. Recently the agonist, BNP was shown to be required for the transmission of itch sensation between peripheral and spinal cord nerves. The Npr1 assays will be used to identify antagonists for use in pharmacological treatments of chronic itch, a condition that results in long-term unremitting urge to scratch that significantly degrades the quality of life for sufferers. SIRPa-CD47 Protein-protein interaction. In collaboration with T. Miller (Paradigm Shift Therapeutics) and D. Roberts (NCI, NIH) our goal is to leverage the broad potential of CD47 as a molecular target in a number of tumors to create therapeutics that protect normal tissue from chemo and radiation therapy while differentially enhancing the effects of these therapies on the tumor. We are currently reengineering a medium throughput biochemical CD47 ligand binding assay to a higher throughput system capable of screening a larger number of molecules.

该项目包括基于与疾病相关的特定蛋白质或核酸靶点开发生化和靶向检测方法。检测设计是在分析和进展策略的背景下考虑的，用于使用高通量筛选技术评估各种化合物类别。非常重视方法开发研究，以提高检测和先导化合物发现效率。为了补充这些活动，我们还探索和设计了复杂化学库（例如天然产物提取物、mRNA 展示）的询问方法。该计划的工作用于支持一系列拨款申请和原型项目。 以下内容正在进行中： Radixin 介导的 cAMP 效应子组装。 cAMP 是一种通用的第二信使，每种细胞类型中的多种激素都使用它。它涉及正常生理和疾病的多个方面，因此是药物发现的有效但具有挑战性的目标。我们与 D. Altschuler（美国匹兹堡大学）合作，正在研究专门针对参与 cAMP 依赖性细胞增殖的 cAMP 效应器-支架复合物的检测策略。 用小分子靶向蛋白质棕榈酰化。我们与 A. Banerjee（NICHD、NIH）合作，正在开发 1536 孔兼容的蛋白质棕榈酰酰基转移酶测定法，以评估该酶的潜在抑制剂的化学库，作为此类酶所导致的大量疾病的可能治疗方法。已链接。 预计这些化合物也具有作为结构、功能和药理学探针的价值。 发现 RNA 小分子配体的策略。我们与 N. Baird 教授（美国科学学院）合作，正在探索检测设计，以探测小分子与非编码基因调节 mRNA 的相互作用。该研究具有发现新型抗生素或抗癌药物的潜力。 开发检测方法以发现受体鸟苷酸环化酶 Npr1 的新型小分子拮抗剂。我们与 M. Hoon（NIDCR、NIH）合作，正在开发和测试 b 型利钠肽 (BNP) 受体 Npr1 的新检测方法。 最近，BNP 激动剂被证明是外周神经和脊髓神经之间瘙痒感传递所必需的。 Npr1 检测将用于鉴定用于慢性瘙痒药物治疗的拮抗剂，慢性瘙痒是一种导致长期持续不断的抓挠冲动的疾病，从而显着降低患者的生活质量。 SIRPa-CD47 蛋白质-蛋白质相互作用。与 T. Miller（Paradigm Shift Therapeutics）和 D. Roberts（NCI、NIH）合作，我们的目标是利用 CD47 作为多种肿瘤分子靶点的广泛潜力，创造出保护正常组织免受化疗和放疗影响的治疗方法疗法，同时差异化地增强这些疗法对肿瘤的效果。 我们目前正在将中等通量生化 CD47 配体结合测定重新设计为能够筛选更多分子的更高通量系统。