Platinum-Acridine Agents with High Activity in Cancers Expressing the Solute Carrier MATE1 ().

Platinum-acridine anticancer agents (PAs) containing acyclic ( and ) and heterocyclic ()-3-aminopiperidine () and 2-iminopyrrolidine () based linker moieties were studied. Similar to , rigidified shows a strong positive correlation between potency and (multidrug and toxin extrusion protein 1, MATE1) gene expression levels across the NCI-60 panel of cancer cell lines. All derivatives show nanomolar activity in HepG2 (liver), NCI-H460 (lung), and MDA-MB-436 (breast), which express high levels of (Cancer Cell Line Encyclopedia, CCLE). The PAs are up to 350-fold more potent than cisplatin. In a MATE1 inhibition assay, a significant reduction in activity is observed in the three cancer cell lines (4000-fold lower for HepG2). Molecular docking experiments provide insight into the compatibility of the structurally diverse set of PAs with MATE1-mediated transport. MATE1 is a predictive marker and actionable target that sensitizes cancer cells regardless of the tissue of origin to PAs.