Work

Benzoic Acid Derivatives Improve Plasma Stability of Diester Butyrophilin Ligand Prodrugs

Year: 2026

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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, EC 50 = 0.86 nM) and interferon γ production in response to loaded K562 cells ( 8d, EC 50 = 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c03034