Classes of Drugs that Mitigate Radiation Syndromes
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 lymphocy...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.666776/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Ewa D. Micewicz Robert D. Damoiseaux Robert D. Damoiseaux Robert D. Damoiseaux Gang Deng Adrian Gomez Keisuke S. Iwamoto Michael E. Jung Christine Nguyen Andrew J. Norris Josephine A. Ratikan Piotr Ruchala James W. Sayre Dörthe Schaue Julian P. Whitelegge William H. McBride |
| spellingShingle |
Ewa D. Micewicz Robert D. Damoiseaux Robert D. Damoiseaux Robert D. Damoiseaux Gang Deng Adrian Gomez Keisuke S. Iwamoto Michael E. Jung Christine Nguyen Andrew J. Norris Josephine A. Ratikan Piotr Ruchala James W. Sayre Dörthe Schaue Julian P. Whitelegge William H. McBride Classes of Drugs that Mitigate Radiation Syndromes Frontiers in Pharmacology radiation mitigators hematopoietic acute radiation syndrome gastro-intestinal acute radiation syndrome delayed effects of radiation exposure multi-organ disease syndrome High throughput screening |
| author_facet |
Ewa D. Micewicz Robert D. Damoiseaux Robert D. Damoiseaux Robert D. Damoiseaux Gang Deng Adrian Gomez Keisuke S. Iwamoto Michael E. Jung Christine Nguyen Andrew J. Norris Josephine A. Ratikan Piotr Ruchala James W. Sayre Dörthe Schaue Julian P. Whitelegge William H. McBride |
| author_sort |
Ewa D. Micewicz |
| title |
Classes of Drugs that Mitigate Radiation Syndromes |
| title_short |
Classes of Drugs that Mitigate Radiation Syndromes |
| title_full |
Classes of Drugs that Mitigate Radiation Syndromes |
| title_fullStr |
Classes of Drugs that Mitigate Radiation Syndromes |
| title_full_unstemmed |
Classes of Drugs that Mitigate Radiation Syndromes |
| title_sort |
classes of drugs that mitigate radiation syndromes |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Pharmacology |
| issn |
1663-9812 |
| publishDate |
2021-05-01 |
| description |
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. |
| topic |
radiation mitigators hematopoietic acute radiation syndrome gastro-intestinal acute radiation syndrome delayed effects of radiation exposure multi-organ disease syndrome High throughput screening |
| url |
https://www.frontiersin.org/articles/10.3389/fphar.2021.666776/full |
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doaj-51771cf263924ecca3296a531a0d3deb2021-05-18T04:39:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-05-011210.3389/fphar.2021.666776666776Classes of Drugs that Mitigate Radiation SyndromesEwa D. Micewicz0Robert D. Damoiseaux1Robert D. Damoiseaux2Robert D. Damoiseaux3Gang Deng4Adrian Gomez5Keisuke S. Iwamoto6Michael E. Jung7Christine Nguyen8Andrew J. Norris9Josephine A. Ratikan10Piotr Ruchala11James W. Sayre12Dörthe Schaue13Julian P. Whitelegge14William H. McBride15Department of Radiation Oncology, University of California at Los Angeles, Los Angeles, CA, United StatesCalifornia NanoSystems Institute, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Bioengineering, Henry Samueli School of Engineering, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, CA, United StatesPasarow Mass Spectrometry Laboratory, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Radiation Oncology, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Radiation Oncology, University of California at Los Angeles, Los Angeles, CA, United StatesBCN Biosciences, LLC, Pasadena, CA, United StatesDepartment of Radiation Oncology, University of California at Los Angeles, Los Angeles, CA, United StatesPasarow Mass Spectrometry Laboratory, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Biostatistics and Radiology, Fielding School of Public Health, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Radiation Oncology, University of California at Los Angeles, Los Angeles, CA, United StatesPasarow Mass Spectrometry Laboratory, University of California at Los Angeles, Los Angeles, CA, United StatesDepartment of Radiation Oncology, University of California at Los Angeles, Los Angeles, CA, United StatesWe 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.https://www.frontiersin.org/articles/10.3389/fphar.2021.666776/fullradiation mitigatorshematopoietic acute radiation syndromegastro-intestinal acute radiation syndromedelayed effects of radiation exposuremulti-organ disease syndromeHigh throughput screening |