Ligand supplementation restores the cancer therapy efficacy of an 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 found that auranofin supplemented with its own thiol ligand, TGTA (1-thio-β-D-glucose tetraacetate), significantly restored the anticancer activities in cells and patient-derived xenograft models. Then, screening a collection of ligand fragments followed by machine learning evaluation unveiled diverse synergizing thiols, including pantethine that effectuates auranofin at a low dosage used for rheumatoid arthritis. Interestingly, the thiol exchange inside cells accounts for a cuproptosis-like phenotype induced by auranofin. 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. ### Competing Interest Statement Y.W., X.X., A.S.C.C., and T.Z. hold patents related to combo treatment by auranofin and thiols/disulfides.