Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity
IntroductionTNFα inhibitor (TNFi) immunogenicity in rheumatoid arthritis (RA) is a major obstacle to its therapeutic effectiveness. Although methotrexate (MTX) can mitigate TNFi immunogenicity, its adverse effects necessitate alternative strategies. Targeting nuclear factor of activated T cells (NFA...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1397995/full |
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| author | Aboli Bhingarkar Yuyin Wang Keito Hoshitsuki Katherine Marie Eichinger Katherine Marie Eichinger Sanjay Rathod Yin Zhu He Lyu Andrew T. McNutt Larry W. Moreland Lee McDermott David R. Koes Christian A. Fernandez |
| author_facet | Aboli Bhingarkar Yuyin Wang Keito Hoshitsuki Katherine Marie Eichinger Katherine Marie Eichinger Sanjay Rathod Yin Zhu He Lyu Andrew T. McNutt Larry W. Moreland Lee McDermott David R. Koes Christian A. Fernandez |
| author_sort | Aboli Bhingarkar |
| collection | DOAJ |
| description | IntroductionTNFα inhibitor (TNFi) immunogenicity in rheumatoid arthritis (RA) is a major obstacle to its therapeutic effectiveness. Although methotrexate (MTX) can mitigate TNFi immunogenicity, its adverse effects necessitate alternative strategies. Targeting nuclear factor of activated T cells (NFAT) transcription factors may protect against biologic immunogenicity. Therefore, developing a potent NFAT inhibitor to suppress this immunogenicity may offer an alternative to MTX.MethodsWe performed a structure-based virtual screen of the NFATC2 crystal structure to identify potential small molecules that could interact with NFATC2. For validation, we investigated the effect of the identified compound on NFAT transcriptional activity, nuclear localization, and binding to the NFAT consensus sequence. In vivo studies assessed the ability of the compound to protect against TNFi immunogenicity, while ex vivo studies evaluated its effect on CD4+ T cell proliferation and B cell antibody secretion.ResultsWe identified duvelisib (DV) as a novel NFATC2 and NFATC1 inhibitor that attenuates NFAT transcriptional activity without inhibiting calcineurin or NFAT nuclear localization. Our results suggest that DV inhibits NFAT independently of PI3K by interfering with nuclear NFAT binding to the NFAT consensus promoter sequence. DV significantly protected mice from adalimumab immunogenicity and attenuated ex vivo CD4+ T cell proliferation and B cell antibody secretion.DiscussionDV is a promising NFAT inhibitor that can protect against TNFi immunogenicity without inhibiting calcineurin phosphatase activity. Our results suggest that the future development of DV analogs may be of interest as agents to attenuate unwanted immune responses. |
| format | Article |
| id | doaj-art-33b8517d55b4427c99069835ddbabc64 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-33b8517d55b4427c99069835ddbabc642025-01-09T06:10:21ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.13979951397995Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicityAboli Bhingarkar0Yuyin Wang1Keito Hoshitsuki2Katherine Marie Eichinger3Katherine Marie Eichinger4Sanjay Rathod5Yin Zhu6He Lyu7Andrew T. McNutt8Larry W. Moreland9Lee McDermott10David R. Koes11Christian A. Fernandez12Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesDuo Oncology, Pittsburgh, PA, United StatesCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesDepartment of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United StatesDivision of Rheumatology, School of Medicine, University of Colorado, Aurora, CO, United StatesDepartment of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesDepartment of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United StatesCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United StatesIntroductionTNFα inhibitor (TNFi) immunogenicity in rheumatoid arthritis (RA) is a major obstacle to its therapeutic effectiveness. Although methotrexate (MTX) can mitigate TNFi immunogenicity, its adverse effects necessitate alternative strategies. Targeting nuclear factor of activated T cells (NFAT) transcription factors may protect against biologic immunogenicity. Therefore, developing a potent NFAT inhibitor to suppress this immunogenicity may offer an alternative to MTX.MethodsWe performed a structure-based virtual screen of the NFATC2 crystal structure to identify potential small molecules that could interact with NFATC2. For validation, we investigated the effect of the identified compound on NFAT transcriptional activity, nuclear localization, and binding to the NFAT consensus sequence. In vivo studies assessed the ability of the compound to protect against TNFi immunogenicity, while ex vivo studies evaluated its effect on CD4+ T cell proliferation and B cell antibody secretion.ResultsWe identified duvelisib (DV) as a novel NFATC2 and NFATC1 inhibitor that attenuates NFAT transcriptional activity without inhibiting calcineurin or NFAT nuclear localization. Our results suggest that DV inhibits NFAT independently of PI3K by interfering with nuclear NFAT binding to the NFAT consensus promoter sequence. DV significantly protected mice from adalimumab immunogenicity and attenuated ex vivo CD4+ T cell proliferation and B cell antibody secretion.DiscussionDV is a promising NFAT inhibitor that can protect against TNFi immunogenicity without inhibiting calcineurin phosphatase activity. Our results suggest that the future development of DV analogs may be of interest as agents to attenuate unwanted immune responses.https://www.frontiersin.org/articles/10.3389/fphar.2024.1397995/fullrheumatoid arthritisantidrug antibodies (ADA)NFAT (nuclear factor of activated T cells)methotrexateadalimumabduvelisib |
| spellingShingle | Aboli Bhingarkar Yuyin Wang Keito Hoshitsuki Katherine Marie Eichinger Katherine Marie Eichinger Sanjay Rathod Yin Zhu He Lyu Andrew T. McNutt Larry W. Moreland Lee McDermott David R. Koes Christian A. Fernandez Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity Frontiers in Pharmacology rheumatoid arthritis antidrug antibodies (ADA) NFAT (nuclear factor of activated T cells) methotrexate adalimumab duvelisib |
| title | Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity |
| title_full | Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity |
| title_fullStr | Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity |
| title_full_unstemmed | Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity |
| title_short | Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity |
| title_sort | duvelisib is a novel nfat inhibitor that mitigates adalimumab induced immunogenicity |
| topic | rheumatoid arthritis antidrug antibodies (ADA) NFAT (nuclear factor of activated T cells) methotrexate adalimumab duvelisib |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1397995/full |
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