Ligand supplementation restores the cancer therapy efficacy of the antirheumatic drug auranofin from serum inactivation.

Auranofin, an FDA-approved antirheumatic gold drug, has gained ongoing interest in clinical studies for treating advanced or recurrent tumors. However, gold ion's dynamic thiol exchange nature strongly attenuates its bioactivity due to the fast formation of covalent albumin-gold adducts. Here we report that newly-added thiols can modulate the dynamic albumin-gold binding and recover the therapeutic efficacy. Initially, we find that auranofin supplemented with its own thiol ligand, TGTA (1-thio-β-D-glucose tetraacetate), significantly restores the anticancer activities in cells and patient-derived xenograft models. Then, screening a collection of ligand fragments followed by machine learning evaluation unveils diverse synergizing thiols, including pantethine, that effectuate auranofin at a low dosage for rheumatoid arthritis. Interestingly, the thiol exchange inside cells accounts for a cuproptosis-like phenotype that auranofin induces. Together, we believe the ligand-enabled dynamic modulation strategy is of value to researchers and clinicians contemplating metallodrugs and ligand-like molecules in cancer therapy.