Platinum–Acridine Agents with High Activity in Cancers Expressing the Solute Carrier MATE1 (SLC47A1)

• Published in: ACS medicinal chemistry letters 2023-08, Vol.14 (8), p.1122-1128
• Main Authors: Zhang, Shenjie, Wu, Haoqing, Day, Cynthia S., Bierbach, Ulrich
• Format: Article
• Language: English
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.3c00266

Platinum–acridine anticancer agents (PAs) containing acyclic (1 and 3) and heterocyclic (R)-3-aminopiperidine (2) and 2-iminopyrrolidine (4) based linker moieties were studied. Similar to 1, rigidified 2 shows a strong positive correlation between potency and SLC47A1 (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 SLC47A1 (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.