Novel Pharmacological Probes Targeting Exchange Proteins Activated by cAMP (EPAC)

针对 cAMP 激活的交换蛋白的新型药理学探针 (EPAC)

• 批准号: 8482964
• 负责人: XIAODONG CHENG
• 金额: $ 49.11万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8482964
• 关键词: Alzheimer' s Disease; Amyloid; Animal Model; Autistic Disorder; Binding; Biochemical; Biological Assay; Biological Process; Biology; Cell physiology; Cells; Chemicals; Collaborations; Cyclic AMP; Cyclic AMP Receptors; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Disease; Docking; Eukaryotic Cell; Family; Fibrosis; Growth; Guanine Nucleotide Exchange Factors; Heart Hypertrophy; Immune response; Inflammation; Intracellular Second Messenger; Knowledge; Laboratories; Lead; Leptin; Libraries; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Medical; Molecular; Muscle Cells; Neoplasm Metastasis; Obesity; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Play; Principal Investigator; Process; Property; Proteins; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Structure-Activity Relationship; Synaptic Transmission; Therapeutic; Tissues; axon regeneration; base; cell motility; design; disease mechanisms study; high throughput screening; human disease; in vitro Assay; in vivo; inhibitor/antagonist; insulin secretion; novel; process optimization; public health relevance; response; screening; small molecule; therapeutic target

DESCRIPTION (provided by applicant): This is an R01 application in response to FOA PAR-12-060 "Solicitation of Validated Hits for the Discovery of in vivo Chemical Probe (R01)". cAMP-mediated cell signaling regulates a myriad of important biological processes and plays important roles in the development of many human diseases. In eukaryotic cells, the effects of cAMP are mainly transduced by two groups of intracellular cAMP receptors, the classic protein kinase A/cAMP-dependent protein kinase (PKA/cAPK) and a new family of more recently discovered exchange proteins directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor (EPACs/cAMP-GEFs). One of the major challenges within the research field is the lack of EPAC specific antagonists for interrogating the biological functions of EPACs in physiological setting and for understanding of disease mechanisms in which EPACs are implicated. To bridge this gap, we have identified and validated several novel, first-in-class small chemical antagonists specific for EPACs. In the present proposal, we will build on the validated hits discovered in our laboratory as the lead candidates and design, synthesize and evaluate more potent and specific EPAC specific probes. Optimized EPAC chemical probes that effectively inhibit EPAC signaling in biochemical and cell-based assays will be analyzed in vivo in animal models to identify potential target molecules for development of EPAC-based therapeutics. The proposed studies build upon an ongoing, proven productive collaboration between two principal investigators with extensive complimentary expertise in EPAC/cAMP biology and medicinal chemistry, respectively. The interdisciplinary perspectives, new chemical entities and emerging medical importance of EPAC will lead to the discovery of a new class of in vivo chemical probes that can be used in studying disease mechanisms and treatments related to EPAC signaling.

描述（由申请人提供）：这是响应 FOA PAR-12-060“体内化学探针发现的验证命中征集（R01）”的 R01 申请。 cAMP 介导的细胞信号传导调节许多重要的生物过程，并在许多人类疾病的发展中发挥重要作用。在真核细胞中，cAMP 的作用主要由两组细胞内 cAMP 受体转导，即经典蛋白激酶 A/cAMP 依赖性蛋白激酶 (PKA/cAPK) 和最近发现的由 cAMP/cAMP 调节的鸟嘌呤核苷酸交换因子直接激活的新交换蛋白家族 (EPACs/cAMP-GEFs)。研究领域的主要挑战之一是缺乏 EPAC 特异性拮抗剂来探究 EPAC 在生理环境中的生物学功能以及了解 EPAC 所涉及的疾病机制。为了弥补这一差距，我们鉴定并验证了几种针对 EPAC 的新型、一流的小化学拮抗剂。在目前的提案中，我们将以我们实验室发现的经过验证的命中作为主要候选者，设计、合成和评估更有效和更具体的 EPAC 特异性探针。优化的 EPAC 化学探针可在生化和细胞检测中有效抑制 EPAC 信号传导，并将在动物模型体内进行分析，以确定用于开发基于 EPAC 的疗法的潜在靶分子。拟议的研究建立在两位分别在 EPAC/cAMP 生物学和药物化学领域拥有广泛互补专业知识的主要研究人员之间正在进行的、经过验证的富有成效的合作的基础上。 EPAC 的跨学科视角、新化学实体和新兴的医学重要性将导致发现一类新型体内化学探针，可用于研究与 EPAC 信号传导相关的疾病机制和治疗。