Development of YK-4-250, a radiation mitigator of GI-ARS - ABSTRACT Gastrointestinal (GI) toxicity remains a significant contributor to mortality following exposure to ionizing radiation (IR), leading to GI Acute Radiation Syndrome (GI-ARS). Current lack of effective therapy for GI-ARS underscores the critical need for medical countermeasures (MCM). This study aims to investigate the mechanisms regulating the renin-angiotensin system (RAS) and reactive oxygen species (ROS) signalling through the AT1 receptor to mitigate GI-ARS. The research introduces a novel, selective and potent Tempol-ARB conjugate, YK-4-250, targeted to the AT1 receptor. Preliminary data show that oral administration of 20 mg/kg YK-4-250 at 24, 48 and 72 hours after exposure to 14.3 Gy partial body irradiation (PBI) significantly mitigated GI-ARS in mice, leading to GI-recovery by day 7 and an 88% overall 30-day survival. The hypothesis postulates that IR activates RAS, elevating Ang II levels, causing oxidative damage and triggering pro-inflammatory cytokine release, ultimately contributing to acute GI-ARS. YK-4-250 is proposed as an effective radiation mitigator, with specific aims including assessing improved safety vehicle formulations, measuring basic in vivo safety, defining pharmacokinetics, determining pharmacodynamics, and evaluating survival efficacy in GI-ARS and pulmonary fibrosis models. Our final aim explores the concept that AT1R knockout mimics YK-4-250 in mitigating GI injury and prolonging post-radiation survival. The study seeks to perform formulation development for YK-4-250 for use in vivo studies, identify molecular mechanisms enhancing cytoprotective function, and investigate its utility in mitigating IR-induced lung fibrosis. Successful completion of these studies is anticipated to advance YK-4-250's development as a effective radiation mitigator for GI-ARS, potentially expanding its application as a broader medical countermeasure.
