Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells.

Autor:	Xu Q; School of Pharmacy and Pharmaceutical Sciences, Cardiff University Cardiff CF10 3NB UK MehellouY1@cardiff.ac.uk., Sharif M; Institute of Immunology and Immunotherapy, University of Birmingham Birmingham B15 2TT UK b.willcox@bham.ac.uk.; Cancer Immunology and Immunotherapy Centre, University of Birmingham Birmingham B15 2TT UK., James E; School of Pharmacy and Pharmaceutical Sciences, Cardiff University Cardiff CF10 3NB UK MehellouY1@cardiff.ac.uk., Dismorr JO; School of Chemistry, University of Birmingham Birmingham B15 2TT UK., Tucker JHR; School of Chemistry, University of Birmingham Birmingham B15 2TT UK., Willcox BE; Institute of Immunology and Immunotherapy, University of Birmingham Birmingham B15 2TT UK b.willcox@bham.ac.uk.; Cancer Immunology and Immunotherapy Centre, University of Birmingham Birmingham B15 2TT UK., Mehellou Y; School of Pharmacy and Pharmaceutical Sciences, Cardiff University Cardiff CF10 3NB UK MehellouY1@cardiff.ac.uk.; Medicines Discovery Institute, Cardiff University Cardiff CF10 3AT UK.
Jazyk:	angličtina
Zdroj:	RSC medicinal chemistry [RSC Med Chem] 2024 Jun 03; Vol. 15 (7), pp. 2462-2473. Date of Electronic Publication: 2024 Jun 03 (Print Publication: 2024).
DOI:	10.1039/d4md00208c
Abstrakt:	The phosphoantigen ( E )-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (>7 h), and their in vitro metabolism was shown to be initiated by carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder cancer cells in vitro . Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents. Competing Interests: Y. M. and B. E. W. are named investors in a patent application covering the prodrugs presented in this work (application number: EP23171966.7). Also, Y. M. and B. E. W. provide consultancy services regarding the development of gamma delta T cell based immunotherapy approaches. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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