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

描述（由申请人提供）：这是响应FOA PAR-12-060“体内化学探针（R 01）发现验证命中请求"的R 01申请。cAMP介导的细胞信号传导调节无数重要的生物学过程，并在许多人类疾病的发展中起重要作用。在真核细胞中，cAMP的作用主要通过两组细胞内cAMP受体转导，经典的蛋白激酶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（EPAC/cAMP-GEF）直接激活的新的交换蛋白家族。研究领域内的主要挑战之一是缺乏EPAC特异性拮抗剂来询问EPAC在生理环境中的生物学功能和理解EPAC所涉及的疾病机制。为了弥合这一差距，我们已经确定并验证了几种新型的，一流的小化学拮抗剂，具体的EPAC。在本提案中，我们将建立在我们实验室中发现的经验证的命中作为主要候选人，并设计，合成和评估更有效和特异性的EPAC特异性探针。在生物化学和基于细胞的测定中有效抑制EPAC信号传导的优化的EPAC化学探针将在动物模型中进行体内分析，以鉴定用于开发基于EPAC的治疗剂的潜在靶分子。拟议的研究建立在两名主要研究者之间正在进行的、经证明的富有成效的合作基础上，这两名主要研究者分别在EPAC/cAMP生物学和药物化学方面具有广泛的互补专业知识。EPAC的跨学科视角、新的化学实体和新兴的医学重要性将导致发现一类新的体内化学探针，其可用于研究与EPAC信号传导相关的疾病机制和治疗。

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.