Journal article
Benzoic Acid Derivatives Improve Plasma Stability of Diester Butyrophilin Ligand Prodrugs
Journal of medicinal chemistry, Vol.69(4), pp.4329-4345
02/26/2026
DOI: 10.1021/acs.jmedchem.5c03034
PMID: 41680590
Abstract
The potent butyrophilin ligand, (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), is a potential cancer immunotherapy agent, but it lacks plasma stability and membrane permeability. Aryl phosphonamidate prodrugs of a key HMBPP analog have improved plasma stability but poor cellular uptake, while aryl phosphonester prodrugs have improved uptake but lack plasma stability. Here, tuning the benzoic acid substructure of a phosphonester prodrug was explored. Twenty-one aryl phosphonester derivatives were prepared in allylic alcohol (8a–k) and allylic acetate (9a–k) forms. Testing revealed that this strategy can provide compounds with high potency for expansion of γ9δ2 T cells (8d, EC50 = 0.86 nM) and interferon γ production in response to loaded K562 cells (8d, EC50 = 2.3 nM). Importantly, these compounds display improved plasma stability (130-fold range; 8d, t 1/2 > 24 h), showing the importance of the benzoic acid position for plasma versus cellular metabolism. These findings enable next-generation prodrugs with improved stability and potency.
Details
- Title: Subtitle
- Benzoic Acid Derivatives Improve Plasma Stability of Diester Butyrophilin Ligand Prodrugs
- Creators
- Parker A. Kintigh - University of IowaUmed Singh - University of IowaGirija Pawge - University of ConnecticutSidra Bashir - University of ConnecticutChia-Hung Christine Hsiao - University of ConnecticutAndrew J. Wiemer - University of ConnecticutDavid F. Wiemer - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.69(4), pp.4329-4345
- DOI
- 10.1021/acs.jmedchem.5c03034
- PMID
- 41680590
- NLM abbreviation
- J Med Chem
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Publisher
- American Chemical Society
- Number of pages
- 17
- Grant note
- National Cancer Institute: CA266138
We acknowledge the assistance from the University of Connecticut Proteomics & Metabolomics Facility with the LMCS analysis. We appreciate the assistance of the University of Connecticut Flow Cytometry Facility with the flow cytometry experiments. Research reported herein was supported by a grant from the National Cancer Institute of the United States National Institutes of Health (CA266138 to A.J.W.).
- Language
- English
- Date published
- 02/26/2026
- Academic Unit
- Chemistry
- Record Identifier
- 9985139301102771
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