Classes of Drugs that Mitigate Radiation Syndromes

Abstract

We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the full analysis of the HTS screen of libraries with 85,000 small molecule chemicals that identified 220 “hits.” Most of these hits could be allocated by maximal common substructure analysis to one of 11 clusters each containing at least three active compounds. Further screening validated 23 compounds as being most active; 15 of these were cherry-picked based on drug availability and tested for their ability to mitigate acute hematopoietic radiation syndrome (H-ARS) in mice. Of these, five bore a 4-nitrophenylsulfonamide motif while 4 had a quinoline scaffold. All but two of the 15 significantly (p < 0.05) mitigated H-ARS in mice. We had previously reported that the lead 4-(nitrophenylsulfonyl)-4-phenylpiperazine compound (NPSP512), was active in mitigating multiple acute and late radiation syndromes in mice of more than one sex and strain. Unfortunately, the formulation of this drug had to be changed for regulatory reasons and we report here on the synthesis and testing of active analogs of NPSP512 (QS1 and 52A1) that have increased solubility in water and in vivo bioavailability while retaining mitigator activity against H-ARS (p < 0.0001) and other radiation syndromes. The lead quinoline 057 was also active in multiple murine models of radiation damage. Taken together, HTS of a total of 150,000 bioactive or chemical substances, combined with maximal common substructure analysis has resulted in the discovery of diverse groups of compounds that can mitigate H-ARS and at least some of which can mitigate multiple radiation syndromes when given starting 24 h after exposure. We discuss what is known about how these agents might work, and the importance of formulation and bioavailability.

NRF2 Mediates Cellular Resistance to Transformation, Radiation, and Inflammation in Mice

“…Previously, we reported on survival of WT and Nrf2–/– gnotobiotic mice given a range of WBI doses where we performed the appropriate SAS probit analysis for radiation dose-related lethality. We found that the LD50/30 for hematopoietic acute radiation syndrome (hARS) between day 10–30 was reduced to 7.0 Gy in Nrf2–/– , as opposed to 8.2 Gy for WT controls [ 46 ]. These data allowed us to give isoeffective survival WBI doses to WT and Nrf2–/– mice and test if the activity of one of our most powerful 4-nitrophenylsulfonamide hARS mitigators, BCN512, [ 46 ] was Nrf2-dependent.…”

“…We found that the LD50/30 for hematopoietic acute radiation syndrome (hARS) between day 10–30 was reduced to 7.0 Gy in Nrf2–/– , as opposed to 8.2 Gy for WT controls [ 46 ]. These data allowed us to give isoeffective survival WBI doses to WT and Nrf2–/– mice and test if the activity of one of our most powerful 4-nitrophenylsulfonamide hARS mitigators, BCN512, [ 46 ] was Nrf2-dependent. BCN512 was inactive in Nrf2–/– mice, even though they were given lower WBI doses, while it almost completely protected WT mice from hARS lethality when given daily for 5 days starting 24 h after WBI ( Figure 1 D).…”

“…Literature reports have also suggested a NRF2 dependency of certain other hARS mitigators [ 44 , 61 , 62 , 63 , 64 ]. In the case of BCN512 there is evidence that it acts through enhancing myelopoiesis after WBI [ 46 ], a process that involves cytokines and chemokines, which may be under NRF2 control.…”

“…However, IR-induced NRF2 activation is not always rapid and is often delayed by many days [ 44 ], suggesting that initial ROS production is less relevant than later events. Indeed, while Nrf2–/– MEFs and mice are more radiosensitive than WT [ 41 , 44 , 45 , 46 ], immediate NRF2 responses induced by chemical agents [ 41 , 47 ] may not necessarily cytoprotect cells against IR [ 41 ]. This suggests that the oxidative stress induced by IR and downstream Nrf2 antioxidant production has many complexities but little is known about the roles of delayed NRF2 responses in the many biological processes thought to be under NRF2 control.…”

Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome

“…The hematopoietic system, consisting of highly proliferative stem cells, stands out as one of the most susceptible organ to radiation-induced injury [ 47 ]. In established animal models for TBI, four FDA-approved drugs targeting the hematopoietic system–Neupogen, Neulasta, Leukine, and Nplate (Romiplostim)-have demonstrated efficacy in increasing HSPCs in irradiated animals [ 2 , 48 – 50 ]. However, their activity regulating the BM microenvironment for HSPC regeneration remains unexplored.…”