IND-Enabling Preclinical Development of a New Radiomitigator

IND 促进新型放射缓解剂的临床前开发

• 批准号: 9280853
• 负责人: GABOR J TIGYI
• 金额: $ 43.64万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280853
• 关键词: Agonist; Benzoic Acids; Blood; Bone Marrow; Budgets; Chemistry; Cost Sharing; Data; Development; Development Plans; Devices; Dose; Drug Kinetics; Drug Targeting; Edg4 Protein; Emergency Situation; Explosion; FDA approved; Feedback; Fukushima; G-Protein-Coupled Receptors; Goals; Grant; Half-Life; Hematopoietic; Hour; In Vitro; Intellectual Property; Isomerism; Lead; Length; Ligands; Lipids; Lysophosphatidic Acid Receptors; Macaca mulatta; Methods; Molecular; Mus; Nuclear; Nuclear Accidents; Partition Coefficient; Pharmaceutical Chemistry; Pharmaceutical Preparations; Placebos; Property; Radiation; Radiation Injuries; Radiation Toxicity; Radiation exposure; Regimen; Research; Resources; Specificity; Structure; Tennessee; Terrorism; Therapeutic; Toxic effect; Toxicology; Universities; Whole-Body Irradiation; Work; analog; animal rule; base; design; drug development; efficacy study; experience; gastrointestinal; improved; in vivo; industry partner; inorganic phosphate; irradiation; lysophosphatidic acid; meetings; molecular mass; mortality; mouse model; phosphonate; preclinical development; preclinical evaluation; public health relevance; receptor; scaffold; small molecule; specific biomarkers; success; thiophosphate; treatment group

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.

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，对基于 RP239 先导结构的新型小分子放射缓解剂进行 IND 药物开发。 Inc. 这一目标源于一项长达十年的放射缓解剂研究，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 (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。该提案建立在我们过去开发十八碳烯基硫代磷酸酯 (OTP) 作为胃肠道急性放射综合征 (GI-ARS) 放射缓解剂的经验和成功的基础上。授权给 RxBio Inc. 的 OTP 于 2011 年在 BARDA 的赞助下进入 FDA 监管管道。 在 LD90/8-10 (16.59 Gy) 局部 γ 射线照射后+24 小时应用 RP239 并进行 5% 骨髓屏蔽，可使胃肠道急性放射综合征 (ARS) 小鼠的死亡率降低 72%（存活率为 11/14，安慰剂组为 1/14）。 RP239 及其类似物也能有效降低造血 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，RP239治疗组的小鼠有50%存活，而安慰剂组只有21%。其类似药物的特性，加上其对 LPA2 受体的特异性以及治疗剂量下无毒性，使我们推测 RP239 应该作为高水平辐射引起的混合 ARS 的有效放射缓解剂进行进一步评估。我们在 OTP 开发方面的独特资源和经验使我们有资格在 RP239 的开发道路上处于领先地位，这将使这种新型放射缓解剂有资格根据动物规则获得 FDA 的快速跟踪。