Classes of Drugs that Mitigate Radiation Syndromes
Ewa D Micewicz1, Robert D Damoiseaux2,3,4, Gang Deng5
1Department of Radiation Oncology, University of California at Los Angeles, Los Angeles, CA, United States.
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.
Insights
This study identified novel drug compounds that mitigate radiation syndromes in mice. Key findings include the discovery of 4-nitrophenylsulfonamide and quinoline scaffolds with significant therapeutic potential for radiation injury.
Area of Science:
- Pharmacology and Toxicology
- Radiation Biology
- Medicinal Chemistry
Background:
- Previous research identified drug classes mitigating radiation syndromes in mice.
- High-throughput screening (HTS) using ionizing radiation-induced lymphocytic apoptosis as a readout identified initial drug candidates.
Purpose of the Study:
- To report the full analysis of an HTS screen of 85,000 small molecule chemicals.
- To validate and characterize compounds mitigating acute hematopoietic radiation syndrome (H-ARS) and other radiation syndromes.
- To synthesize and test novel analogs of a lead compound with improved formulation and bioavailability.
Main Methods:
- Conducted HTS of 85,000 small molecule chemicals to identify drug "hits."
- Utilized maximal common substructure analysis to cluster active compounds.
- Validated 23 compounds, then tested 15 for H-ARS mitigation in mice.
- Synthesized and evaluated water-soluble analogs (QS1, 52A1) of a previously identified lead compound (NPSP512).
Main Results:
- Identified 220 "hits" from the HTS screen, clustering into 11 groups.
- 15 compounds significantly mitigated H-ARS in mice; notable scaffolds included 4-nitrophenylsulfonamide and quinoline.
- Developed novel analogs (QS1, 52A1) with enhanced solubility and bioavailability, retaining significant H-ARS mitigation activity (p < 0.0001).
- A lead quinoline compound (057) demonstrated activity in multiple murine radiation damage models.
Conclusions:
- HTS and substructure analysis successfully discovered diverse compound groups mitigating H-ARS and other radiation syndromes.
- The identified 4-nitrophenylsulfonamide and quinoline compounds represent promising therapeutic agents for radiation injury.
- Optimized analogs demonstrate the importance of formulation and bioavailability for effective in vivo radiation mitigation.
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