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Aryloxy diester phosphonamidate prodrugs of phosphoantigens (ProPAgens) as potent activators of Vγ9/Vδ2 T-Cell immune responses

Kadri, Hachemi, Taher, Taher E., Xu, Qin, Sharif, Maria, Ashby, Elizabeth, Bryan, Richard T., Willcox, Benjamin E. and Mehellou, Youcef ORCID: 2020. Aryloxy diester phosphonamidate prodrugs of phosphoantigens (ProPAgens) as potent activators of Vγ9/Vδ2 T-Cell immune responses. Journal of Medicinal Chemistry 63 (19) , pp. 11258-11270. 10.1021/acs.jmedchem.0c01232

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Vγ9/Vδ2 T-cells are activated by pyrophosphate-containing small molecules known as phosphoantigens (PAgs). The presence of the pyrophosphate group in these PAgs has limited their drug-like properties because of its instability and polar nature. In this work, we report a novel and short Grubbs olefin metathesis-mediated synthesis of methylene and difluoromethylene monophosphonate derivatives of the PAg (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBP) as well as their aryloxy diester phosphonamidate prodrugs, termed ProPAgens. These prodrugs showed excellent stability in human serum (t1/2 > 12 h) and potent activation of Vγ9/Vδ2 T-cells (EC50 ranging from 5 fM to 73 nM), which translated into sub-nanomolar γδ T-cell-mediated eradication of bladder cancer cells in vitro. Additionally, a combination of in silico and in vitro enzymatic assays demonstrated the metabolism of these phosphonamidates to release the unmasked PAg monophosphonate species. Collectively, this work establishes HMBP monophosphonate ProPAgens as ideal candidates for further investigation as novel cancer immunotherapeutic agents.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: American Chemical Society
ISSN: 0022-2623
Funders: Wellcome Trust
Date of First Compliant Deposit: 1 October 2020
Date of Acceptance: 15 September 2020
Last Modified: 09 May 2023 15:59

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