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.
Our study focuses on developing novel chemical probes specifically targeting an important signaling protein that has been implicated in many human diseases including pancreatic cancer. These new chemical probes can be used in studying disease mechanisms and in developing medications.
|Almahariq, Muayad; Mei, Fang C; Cheng, Xiaodong (2016) The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention. Acta Biochim Biophys Sin (Shanghai) 48:75-81|
|Singhmar, Pooja; Huo, XiaoJiao; Eijkelkamp, Niels et al. (2016) Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1. Proc Natl Acad Sci U S A 113:3036-41|
|Wild, Christopher T; Zhu, Yingmin; Na, Ye et al. (2016) Functionalized N,N-Diphenylamines as Potent and Selective EPAC2 Inhibitors. ACS Med Chem Lett 7:460-4|
|Banerjee, Upasana; Cheng, Xiaodong (2015) Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics. Gene 570:157-67|
|Almahariq, Muayad; Chao, Celia; Mei, Fang C et al. (2015) Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo. Mol Pharmacol 87:142-9|
|Zhu, Yingmin; Chen, Haijun; Boulton, Stephen et al. (2015) Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window". Sci Rep 5:9344|
|Ye, Na; Zhu, Yingmin; Chen, Haijun et al. (2015) Structure-Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists. J Med Chem 58:6033-47|
|Chen, Haijun; Wild, Christopher; Zhou, Xiaobin et al. (2014) Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC). J Med Chem 57:3651-65|
|Almahariq, Muayad; Mei, Fang C; Cheng, Xiaodong (2014) Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends Endocrinol Metab 25:60-71|
|Tao, Xinrong; Mei, Feng; Agrawal, Anurodh et al. (2014) Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus. J Virol 88:3902-10|
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