IND-Enabling Preclinical Development of a New Radiomitigator

描述(由申请人提供)：该项目的总体目标是通过田纳西大学和RxBio之间的合作伙伴关系，进行基于RP239铅结构的新型小分子放射增强剂的IND药物开发。这一目标源于一项长达十年的放射治疗研究，该研究确定并验证了溶血磷脂酸(LPA)G蛋白偶联受体(GPCR2)亚型(LPA2)作为放射缓解的治疗药物靶点。RP239是LPA2的特异性小分子激动剂。这项建议建立在我们过去的经验和成功开发十八烯基硫代磷酸(OTP)作为胃肠道急性辐射综合征(GI-ARS)的放射增强剂的基础上。授权给RxBio Inc.的OTP于2011年在BARDA的赞助下进入FDA的监管渠道。 5%骨髓屏蔽剂+LD90/8-10(16.59GyLD90/8-10)γ照射后24小时应用RP239可使胃肠道急性放射综合征小鼠死亡率降低72%(11/14存活率低于安慰剂组1/14)。RP239及其类似物也能有效降低造血性ARS的死亡率。重要的是，当治疗推迟到全身照射后+48h时，RP239治疗组小鼠存活率为50%，而安慰剂组为21%。它的药物样特性，再加上它对LPA2受体的特异性，以及在治疗剂量下的毒性，使我们假设RP239应该被进一步评估为高水平辐射诱发的混合ARS的有效放射增强剂。我们在OTP开发方面的独特资源和经验为我们提供了在开发道路上领先RP239的资格，这将使这种新的放射性增强剂有资格获得FDA根据动物规则进行快速跟踪的资格。

DESCRIPTION (provided by applicant): The overall objective of this project is to conduct IND-enabling drug development of a new small molecule radiomitigator based on the RP239 lead structure thru a partnership between the University of Tennessee and RxBio. Inc. This objective originates from a decade-long radiomitigator research that identified and validated the lysophosphatidic acid (LPA) G protein-coupled receptor (GPCR) subtype 2 (LPA2) as a therapeutic drug target for radiomitigation. RP239 is a specific small molecule agonist of LPA2. This proposal builds on our past experience and success developing octadecenyl thiophosphate (OTP) as a radiomitigator of the gastrointestinal acute radiation syndrome (GI-ARS). OTP licensed to RxBio Inc. was entered into the FDA regulatory pipeline under the sponsorship of BARDA in 2011. RP239 when applied +24h after LD90/8-10 (16.59 Gy) partial-body γ-irradiation with 5% bone marrow shielding reduced mortality of mice from the gastrointestinal acute radiation syndrome (ARS) by 72% (11/14 survival vs. 1/14 in placebo). RP239 and its analogs were also effective in reducing mortality due to the hematopoietic ARS. Importantly, when treatment was delayed to +48h post-total body irradiation, 50% of the mice survived in the RP239 treatment group compared to 21% in the placebo group. Its drug-like properties, combined with its specificity to the LPA2 receptor and lack of toxicity at therapeutic doses lead us to hypothesize that RP239 should be further evaluated as a potent radiomitigator of the mixed ARS elicited by high-levels of radiation. Our unique resources and experience with the development of OTP provide us with qualifications to take the RP239 lead on a development path that will qualify this new radiomitigator for fast tracking by the FDA under the animal rule.