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 ?-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.
There are FDA-approved countermeasures available to deal with the looming threat of a nuclear accident like the one at Fukushima or explosion of a nuclear device, which necessitates the development of radiation countermeasures that are safe and effective when applied 24h or later after radiation injury. Our data with the small molecule RP239 show that it protects mice from very high levels of radiation with remarkable efficacy when applied +24-48 hours after radiation exposure. The goal of this project is the development of a new improved radiomitigator, designated RP239X, for priority or fast-track regulatory approval and inclusion in the Strategic National Stockpile.
|Dancs, Péter Tibor; Ruisanchez, Éva; Balogh, Andrea et al. (2017) LPA1 receptor-mediated thromboxane A2 release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction. FASEB J 31:1547-1555|
|Lin, Kuan-Hung; Ho, Ya-Hsuan; Chiang, Jui-Chung et al. (2016) Pharmacological activation of lysophosphatidic acid receptors regulates erythropoiesis. Sci Rep 6:27050|
|Shukla, Pradeep K; Gangwar, Ruchika; Manda, Bhargavi et al. (2016) Rapid disruption of intestinal epithelial tight junction and barrier dysfunction by ionizing radiation in mouse colon in vivo: protection by N-acetyl-l-cysteine. Am J Physiol Gastrointest Liver Physiol 310:G705-15|
|Ho, Ya-Hsuan; Yao, Chao-Ling; Lin, Kuan-Hung et al. (2015) Opposing regulation of megakaryopoiesis by LPA receptors 2 and 3 in K562 human erythroleukemia cells. Biochim Biophys Acta 1851:172-83|
|Patil, Renukadevi; Szabó, Erzsébet; Fells, James I et al. (2015) Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist. Chem Biol 22:206-16|
|Patil, Renukadevi; Fells, James I; Szabó, Erzsébet et al. (2014) Design and synthesis of sulfamoyl benzoic acid analogues with subnanomolar agonist activity specific to the LPA2 receptor. J Med Chem 57:7136-40|
|Morales-Lázaro, Sara L; Serrano-Flores, Barbara; Llorente, Itzel et al. (2014) Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs. J Biol Chem 289:24079-90|