A New Class of Multitargeting Pt ^IV Anticancer Agents: Prodrugs That Release Pt ^II Drugs and Bioactive Moieties Tethered to Pt ^IV via a Tertiary Amine

In most multi-action Pt^IV prodrugs previously reported, the bioactive molecules have carboxylate, hydroxyl, primary, or secondary amine groups through which they are tethered to the axial position of the Pt^IV directly or via self-immolative linkers. A major challenge is to expand the range to bioactive molecules that can be released in their active form from Pt^IV prodrugs to molecules having a tertiary amine. Herein, we describe the general approach for design and synthesis of Pt^IV complexes conjugated to organic drugs (brigatinib, osimertinib, adavosertib, and irinotecan) via their tertiary amines. The complexes are stable and release the active drugs upon reduction. The Pt^IV prodrugs conjugated to tyrosine kinase inhibitors (TKIs) showed potent anticancer activity in 2D and 3D cancer models by combining the modes of action of platinum and TKi. They inhibited in vivo tumor growth in an LLC model better than brigatinib, osimertinib, and cisplatin with significantly lower body weight loss.