IND-Enabling Preclinical Development of a New Radiomitigator

描述（由申请人提供）：本项目的总体目标是通过田纳西大学和RxBio之间的合作，对基于RP 239先导结构的新型小分子放射性激动剂进行IND使能药物开发。Inc.这一目标源于一项长达十年的放射性激动剂研究，该研究确定并验证了溶血磷脂酸（LPA）G蛋白偶联受体（GPCR）亚型2（LPA 2）作为放射性激动的治疗药物靶点。RP 239是LPA 2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盐（OTP）作为胃肠急性放射综合征（GI-ARS）的放射性拮抗剂。OTP授权给RxBio Inc.在巴尔达的赞助下，于2011年进入FDA监管渠道。 在LD 90/8-10（16.59戈伊）局部γ射线照射后+24小时，使用5%骨髓屏蔽，RP 239使胃肠道急性放射综合征（ARS）小鼠的死亡率降低了72%（11/14存活vs.安慰剂组1/14）。RP 239及其类似物也有效降低了由于造血ARS引起的死亡率。重要的是，当治疗延迟至全身照射后+48小时时，RP 239治疗组中50%的小鼠存活，而安慰剂组中为21%。其药物样性质，结合其对LPA 2受体的特异性和在治疗剂量下缺乏毒性，使我们假设RP 239应进一步评估为高水平辐射引起的混合ARS的有效放射性引发剂。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RP 239的资格，这将使这种新的放射性激动剂有资格获得FDA根据动物规则的快速跟踪。

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.