Development of a Novel Small Molecule as a Radioprotector for Total Body Irradiation

ABSTRACT There are increased needs for effective radiation countermeasures that can protect bone marrowpromote the recovery of hematopoietic stem cellsHSCsor even increase survival rate from radiation induced damage in affected individualsIn generalradiation countermeasures may be divided into two areasradioprotection and radiomitigationThe focus of this project is on broad spectrum radioprotectionCurrentlyamifostine is the only broad spectrum radioprotector approved by the FDA for clinical applicationWhile amifostine effectively reduces normal organ damage caused by radiationit does have serious adverse effects including nauseavomitingand pronounced hypotensionmaking it unacceptable for widespread useAt presentno other small molecule agents have been approved by the FDA as a broad spectrum radioprotectorThereforethere is an urgent need to discover radioprotective agents with higher potency and or fewer side effectsPreviouslywe synthesized a series of small molecule immunomodulatorsUTL compoundsIn animal studieswe found that one of the compoundsUTLgshowed significant radioprotection against acute phase of radiation induced liver injuryUTLg also significantly decreased the apoptosis of liver cells caused by irradiationSubsequentlywe showed that UTLg increased the survival of mice treated with lethal dose of total body irradiationTBIHoweverUTLg is not water solublewhich makes it somewhat difficult for formulation developmentTo make further improvementwe recently used an SARstructure activity relationshipapproach and synthesized a new series of small moleculesUTS compoundsto further improve the radioprotective properties and water solubilityIn a recent studywe found that three of the UTS compounds showed significant radioprotectionAmong these three UTS compoundsUTSshowed the best radioprotective activitymore strikinglyits radioprotective effect is significantly better than that of amifostineThis SBIR Phasestudy is to show the feasibility of developing UTSas a radioprotective agentThere are four specific aims for this PhaseSBIR studyto determine the optimal drug dose of UTSand the optimal TBI dose for the animal studiesto compare the radioprotective effects between UTSand amifostineto investigate the specific protective effects of UTSon TBI induced toxicitiesto conduct a preliminary investigation on the mechanism of actionMOAof UTSAfter the completion of this SBIR PhaseStudywe will have shown the feasibility of developing UTSas a broad spectrum radioprotector for TBIIn the SBIR Phasestudywe will continue the preclinical development of UTSand to complete all essential studies required before an IND filing in order to get ready for clinical trialsThe ultimate goal of this project is to develop UTSas a broad spectrum radioprotector for clinical application and potential nuclear accidents including warfare and related events Narrative The objective of this SBIR Phase I study is to conduct several critical pre clinical studies to show the feasibility to develop a novel small moleculeUTSas a radioprotective agent for total body irradiationThe ultimate goal of this project is to complete the drug development of UTSas a broad spectrum radioprotector that is significantly better than amifostine