Novel Radiomitigators Targeting LPA Receptors

描述（由申请人提供）： 没有FDA批准的符合放射性物质标准的辐射对策-一种在暴露后施用时减轻急性辐射综合征的药剂。本发明的中心假设是溶血磷脂酸受体亚型2（LPA 2）的选择性活化提供了对辐射损伤的保护，即使在辐射暴露后施用。该项目的总体目标是开发第二代针对LPA 2受体的小分子放射性拮抗剂。这一目标是基于十多年的研究，在这些研究中，我们已经确定并验证了溶血磷脂受体作为分子靶点，可以在体外拯救被排斥的细胞，并降低放射损伤后的体内死亡率。 使用基于LPA G蛋白偶联受体的药效团模型的计算机药物发现，我们已经鉴定了两种小的非脂质药物样选择性LPA 2激动剂-GRI 977143和NSC 12404。在初步实验中，我们已经确定GRI 977143在体外保护和拯救培养的细胞免于直接3-辐射诱导的细胞死亡。GRI 977143还可防止将辐照过的U937人组织细胞系培养物的废培养基转移至未辐照过的IEC-6肠上皮细胞或U937细胞培养物引起的“辐射诱导的旁观者细胞凋亡”。当在~7戈伊照射后24 h应用于小鼠时，GRI 977143降低死亡率。然而，这两种化合物的效力是次优的，需要更有效的类似物。 为了建立在这些初步的数据，在这里，我们建议，以确定这些分子支架的类似物，并开发新的非脂质药物样激动剂的LPA GPCR与改善的药理学和药学特性的造血和胃肠道急性放射综合征的缓解。我们将联合收割机结合我们的计算机药物发现专业知识，高通量实验筛选平台，药物化学和制药能力，开发一种新的，更有效的放射性拮抗剂对策。我们建议：1.为LPA 2激动剂实施计算引导的药物发现。2.表征所选非脂质激动剂的体外放射性激动作用。3.评价选定的非脂质激动剂在体内的放射性激动作用。 在战略国家储备中需要放射性物质，以保护我们的军队，第一反应者和公众， 大. VA系统是核事故或恐怖袭击的许多伤亡人员最有可能接受治疗的地方，强调了拟议研究的重要性。

DESCRIPTION (provided by applicant): There is no radiation countermeasure approved by the FDA that meets the criterion of a radiomitigator - an agent, which mitigates the acute radiation syndrome when administered after the exposure. The central hypothesis of the present is that selective activation of the lysophosphatidic acid receptor subtype 2 (LPA2) provides protection against radiation injury even if applied after radiation exposure. The overall objective of this project is to develop a second generation of small molecule radiomitigator countermeasures targeting the LPA2 receptor. This objective is based on over a decade of research, in which we have identified and validated lysophospholipid receptors as molecular targets that rescue apoptotically condemned cells in vitro and decrease mortality in vivo after radiation injury. Using in silico drug discovey based on pharmacophore models of the LPA G protein-coupled receptors, we have identified two small non-lipid drug-like selective LPA2 agonists - GRI977143 and NSC 12404. In preliminary experiments we have established that GRI977143 protects and rescues cultured cell in vitro from direct 3-radiation-induced cell death. GRI977143 also prevents "radiation-induced bystander apoptosis" elicited by the transfer of spent medium of irradiated U937 human histiocytic cell line cultures to non-irradiated IEC-6 intestinal epithelial cell or U937 cell cultres. When applied 24 h after ~7 Gy irradiation in mice, GRI977143 decreased mortality. However, the potency of these two compounds is suboptimal and more potent analogs are needed. To build on these preliminary data, here we propose to identify analogs of these molecular scaffolds and develop novel non-lipid drug-like agonists of the LPA GPCR with improved pharmacological and pharmaceutical properties for the mitigation of the hematopoietic and the gastrointestinal acute radiation syndromes. We will combine our in silico drug discovery expertise, high-throughput experimental screening platforms, medicinal chemistry and pharmaceutics capabilities to develop a new and more effective radiomitigator countermeasure. We propose to: 1. Implement computationally guided drug discovery for LPA2 agonists. 2. Characterize the selected nonlipid agonists for radiomitigating action in vitro. 3. Evaluate the radiomitigating efficacy of selected nonlipid agonists in vivo. Radiomitigators are needed in the Strategic National Stockpile for the protection of our military, first responders and the public at large. The VA System is the likeliest site where many of the casualties of a nuclear accident or terrorist attack would be treated underlining the significance of the proposed research.