The cytotoxicity of cisplatin (cDDP) is enhanced when co-administered with ethacrynic acid (EA), a glutathione S-transferase (GST) inhibitor.APt IV–EA conjugate containing a cDDP core and two axial ethacrynate ligands (compound 1) was shown to be an excellent inhibitor of GST, but did not readily release a PtII species to exert a synergistic cytotoxic effect. In this study,aredesigned PtIV construct composed of a cDDP core with one axial ethacrynate ligand and one axial hydroxido ligand (compound 2) was prepared and shown to overcome the limitations of compound 1. The EA ligand in 2 is readily released in vitro together with a cytotoxic PtII species derived from cisplatin, working together to inhibit cell proliferation in cDDP-resistant human ovarian cancer cells. The in vitro activity translates well in vivo with 2, showing effective (~80%) inhibition of tumor growth in a human ovarian carcinoma A2780 tumor model, while showing considerably lower toxicity than cisplatin, thus validating the new design strategy.