Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy.

David Kreutzer,Christoph A Ritter,Andreas Hilgeroth,Henry Döring,Peter Werner

doi:10.3390/ijms22105098

Abstract

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.

Highlights

Cancer remains the second frequent cause of death worldwide, cancer therapies of the last decades improved by the development of novel drugs and the discovery of novel target structures in cancer cells [1,2,3]
Due to ongoing resistances against anticancer drugs the challenge to combat cancer is the development of novel anticancer drugs that affect novel target structures
The discovery to find effective inhibitors of such efflux pumps would mean a great progress for anticancer therapy

Summary

Introduction

Cancer remains the second frequent cause of death worldwide, cancer therapies of the last decades improved by the development of novel drugs and the discovery of novel target structures in cancer cells [1,2,3]. Ongoing resistances enforced the search for novel structures and resulting drugs [5]. Deregulated protein kinases in cancer cells could be identified and X-ray crystal structure analysis helped to find the binding region for potential inhibitors [6]. Novel small-molecule inhibitors were developed and antibodies were synthesized using biotechnology procedures that address the receptor regions of the respective protein kinases [7]. Mostly single mutations led to changes in the inhibitor binding protein region and cause resistances to the respective drugs [8]. It will be an ongoing challenge to find novel drugs

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Results

Conclusion