Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors
The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinon...
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MDPI AG
2021-06-01
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| Online Access: | https://www.mdpi.com/2218-1989/11/6/390 |
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| author | Noah R. Flynn Michael D. Ward Mary A. Schleiff Corentine M. C. Laurin Rohit Farmer Stuart J. Conway Gunnar Boysen S. Joshua Swamidass Grover P. Miller |
| author_facet | Noah R. Flynn Michael D. Ward Mary A. Schleiff Corentine M. C. Laurin Rohit Farmer Stuart J. Conway Gunnar Boysen S. Joshua Swamidass Grover P. Miller |
| author_sort | Noah R. Flynn |
| collection | DOAJ |
| description | The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 for more in-depth analysis. OXFBD’s bioactivations were evenly split between traditional quinones and novel extended quinone-methides involving the isoxazole yet strongly favored the latter quinones. Subsequent experimental studies confirmed the formation of both types of quinones for OXFBD molecules, yet traditional quinones were the dominant reactive metabolites. Modeled I-BET151 bioactivations led to extended quinone-methides, which were not verified experimentally. The differences in observed and predicted bioactivations reflected the need to improve overall bioactivation scaling. Nevertheless, our coupled modeling approach predicted BET inhibitor bioactivations including novel extended quinone methides, and we experimentally verified those pathways highlighting potential concerns for toxicity in the development of these new drug leads. |
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| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T10:24:58Z |
| publishDate | 2021-06-01 |
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| series | Metabolites |
| spelling | doaj.art-fe2c0e1578ea4615936896f4cf2d13202023-11-22T00:08:45ZengMDPI AGMetabolites2218-19892021-06-0111639010.3390/metabo11060390Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) InhibitorsNoah R. Flynn0Michael D. Ward1Mary A. Schleiff2Corentine M. C. Laurin3Rohit Farmer4Stuart J. Conway5Gunnar Boysen6S. Joshua Swamidass7Grover P. Miller8Department of Pathology and Immunology, Washington University-St. Louis, St. Louis, MO 63130, USADepartment of Pathology and Immunology, Washington University-St. Louis, St. Louis, MO 63130, USADepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Chemistry, University of Oxford, Oxford OX1 3TA, UKDepartment of Pathology and Immunology, Washington University-St. Louis, St. Louis, MO 63130, USADepartment of Chemistry, University of Oxford, Oxford OX1 3TA, UKDepartment of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Pathology and Immunology, Washington University-St. Louis, St. Louis, MO 63130, USADepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USAThe 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 for more in-depth analysis. OXFBD’s bioactivations were evenly split between traditional quinones and novel extended quinone-methides involving the isoxazole yet strongly favored the latter quinones. Subsequent experimental studies confirmed the formation of both types of quinones for OXFBD molecules, yet traditional quinones were the dominant reactive metabolites. Modeled I-BET151 bioactivations led to extended quinone-methides, which were not verified experimentally. The differences in observed and predicted bioactivations reflected the need to improve overall bioactivation scaling. Nevertheless, our coupled modeling approach predicted BET inhibitor bioactivations including novel extended quinone methides, and we experimentally verified those pathways highlighting potential concerns for toxicity in the development of these new drug leads.https://www.mdpi.com/2218-1989/11/6/390bromodomaininhibitorisoxazolemodeldeep neural networkpathway |
| spellingShingle | Noah R. Flynn Michael D. Ward Mary A. Schleiff Corentine M. C. Laurin Rohit Farmer Stuart J. Conway Gunnar Boysen S. Joshua Swamidass Grover P. Miller Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors Metabolites bromodomain inhibitor isoxazole model deep neural network pathway |
| title | Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors |
| title_full | Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors |
| title_fullStr | Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors |
| title_full_unstemmed | Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors |
| title_short | Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors |
| title_sort | bioactivation of isoxazole containing bromodomain and extra terminal domain bet inhibitors |
| topic | bromodomain inhibitor isoxazole model deep neural network pathway |
| url | https://www.mdpi.com/2218-1989/11/6/390 |
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