UTS-1401: A Novel Mitigator of Radiation Injury - Abstract: Our long term objective is to develop a new class of radiation mitigating agents with attractive chemical, physical and biological characteristics required to be an effective drug that can be distributed widely. We have identified a small molecule, UTS-1401 [5-(methylthiomethyl) isoxazole-3-carboxylic acid] which demonstrates mitigation of hematopoietic stem cell death when administered at either 24h or 48h following whole body irradiation (WBI). Using the endogenous spleen colony assay we demonstrated a significant mitigating effect (ratio of colony number with and without UTS-1401) when drug was given 24h or 48h after radiation. We have also recently demonstrated a significant radioprotection for both mouse survival and hematopoietic stem cells for this compound for up to 72h before irradiation (Valeriote et al, Radiation Research, 202:16-25, 2024). In this application, we propose to examine solely the mitigating effect to both the hematopoietic acute radiation syndrome (H-ARS) in specific aim 1 and the gastrointestinal acute radiation syndrome (GI-ARS) in specific aim 2 following WBI (with 5% bone marrow protection for specific aim 2). Swiss mice will receive a series of graded doses of WBI around the LD50 for both syndromes with and without the administration of 150 mg/kg UTS- 1401. The single dose of UTS-1401 being used in all studies is the highest dose administrable due to its aqueous solubility (in tartrate buffered saline). The radiation mitigation factors will be calculated as the ratio of the LD50 for radiation plus UTS-1401 versus radiation alone. The degree of mitigation will be examined at 24, 48 and 72 h following WBI to determine the timeframe of mitigation after radiation exposure. Three routes of drug delivery, intravenous (iv), oral, and subcutaneous (sc), will be examined and compared. For all specific aims, both male and female mice will be separately studied. Radiation will be delivered by electrons from a Linac. In specific aim 3, we will examine the pharmacokinetics (PK) for 150 mg/kg UTS-1401 comparing the iv, oral, and sc routes to obtain a determination of both the drug kinetics and bioavailability. The AUC values will be correlated with the extent of mitigation. Finally, in specific aim 4, we will address the mechanism of action with studies focused on the role of specific cytokines induced by radiation in the so-called “cytokine storm”. We will assess the time course changes of TNF-α, IL-1β, IL-6, CSF and TGF-β in blood as well as bone marrow and intestinal mucosa over 20 days following: UTS-1401 alone, 10 Gy irradiation, and the combination of UTS-1401 and radiation at a 24h interval. The results from these studies are expected to demonstrate an effective first-in-class compound, UTS-1401, which has a small molecular weight, is chemically stable, nontoxic, aqueous soluble and inexpensive with radiation mitigating properties which extend for a number of days following irradiation. The mechanism studies are expected to demonstrate UTS-1401 as a new class of agents for mitigating the cytokine storm consequent to the irradiation.
