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In-VitroGeneration of T-Cell Clones to Difluorophenylglyoxal: Implications for Understanding the Immunogenicity of MK-3207
Journal article   Open access   Peer reviewed

In-VitroGeneration of T-Cell Clones to Difluorophenylglyoxal: Implications for Understanding the Immunogenicity of MK-3207

Paul Thomson, Andrew Gibson, Jackie Shang, Xiaoli Meng, Eleanor Saville, Sophie Grice, Megan Ford, Yu Feng, Kara Pearson, Michael Oropallo, …
Chemical research in toxicology, Vol.39(8), pp.1503-1507
2026
DOI: https://doi.org/10.1021/acs.chemrestox.6c00294
PMID: 42606280
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Open Access CC BY V4.0

Abstract

Chemistry Chemistry, Medicinal Chemistry, Multidisciplinary Life Sciences & Biomedicine Pharmacology & Pharmacy Physical Sciences Science & Technology Toxicology
MK-3207 was withdrawn from development because of drug-induced liver injury. Metabolic studies identified bioactivation to a protein-reactive 3,5-difluorophenylglyoxal (DFPG) intermediate. Although phenylglyoxal metabolites readily form protein adducts, their immunogenic potential has been poorly understood. We compared the immunogenicity of three DFPG isomers (3,5-, 2,4-, and 3,4-DFPG) using T-cell clones generated from treated healthy donor PBMCs. Reactive clones were detected against isomers with 3,5-DFPG inducing the strongest responses. Activation required antigen processing, and no cross-reactivity with MK-3207 was observed. These findings demonstrate the immunogenicity of 3,5-DFPG and show that structural differences among phenylglyoxal isomers influence T cell activation.

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