Novel Radiomitigators Targeting LPA Receptors

描述(由申请人提供)： FDA没有批准的辐射对策符合放射增白剂的标准-放射增强剂是一种在暴露后服用时可以减轻急性辐射综合征的试剂。目前的中心假设是，选择性激活溶血磷脂酸受体亚型2(LPA2)可提供辐射损伤保护，即使在辐射暴露后使用。该项目的总体目标是开发针对LPA2受体的第二代小分子放射增强剂对策。这一目标是基于十多年的研究，在这些研究中，我们已经确认和验证了溶血磷脂受体作为分子靶点，在体外拯救被凋亡的被宣告死亡的细胞，并降低辐射损伤后体内的死亡率。在基于LPAG蛋白偶联受体药效团模型的电子药物研究中，我们鉴定了两种小的非脂类药物样选择性LPA2激动剂-GRI977143和NSC 12404。在初步实验中，我们已经确定GRI977143保护和挽救体外培养的细胞免受直接3-射线诱导的细胞死亡。GRI977143还可防止将辐照后的U937人组织细胞系培养废液转移到未辐照的IEC-6肠上皮细胞或U937细胞培养所引发的“辐射诱导旁观者凋亡”。GRI977143在~7Gy射线照射后24 h给药可降低小鼠死亡率。然而，这两种化合物的效力并不理想，需要更有效的类似物。为了建立在这些初步数据的基础上，我们建议鉴定这些分子支架的类似物，并开发新型的非脂类药物样LPA GPCR激动剂，具有更好的药理和药学特性，用于缓解造血和胃肠道急性放射综合征。我们将结合我们在电子药物发现方面的专业知识、高通量的实验筛选平台、药物化学和药剂学能力，开发一种新的、更有效的放射治疗对策。我们建议：1.实现LPA2激动剂的计算导向药物发现。2.体外鉴定所选非脂类激动剂的放射增敏作用。3.评价所选非脂类激动剂的体内放射防护效果。为了保护我们的军队、急救人员和公众，国家战略储备中需要放射性物质。 大号的。退伍军人管理局是最有可能对核事故或恐怖袭击中的许多伤亡人员进行治疗的地点，这突显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.