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

Xu, Qin, Sharif, Maria, James, Edward, Dismorr, Jack O., Tucker, James H. R., Willcox, Benjamin E. and Mehellou, Youcef ORCID: https://orcid.org/0000-0001-5720-8513 2024. Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells †. RSC Medicinal Chemistry 15 (7) , pp. 2462-2473. 10.1039/d4md00208c

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Medicines Discovery Institute (MDI)
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/3.0/, Start Date: 2024-06-03
Publisher:	Royal Society of Chemistry
ISSN:	2632-8682
Date of First Compliant Deposit:	26 June 2024
Date of Acceptance:	30 May 2024
Last Modified:	01 Aug 2024 13:27
URI:	https://orca.cardiff.ac.uk/id/eprint/170118

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