Development of novel modulators of multidrug resistance (MDR) in cancer cells
Prof. Dr. Andreas Hilgeroth, Peter Werner
Multidrug resistance (MDR) is one of the biggest problems in cancer chemotherapy.
Many types of cancer develop resistance to certain chemotherapeutic agents during treatment, which significantly limits the effectiveness of the therapy and leads to a poor prognosis for the affected patients.
MDR is usually caused by the overexpression of efflux pumps, such as P-glycoprotein (P-gp), which are able to transport a variety of chemotherapeutic agents out of the cell and thus reduce their effectiveness.
Our working group focuses on the development of new diazatetraasterane-type modulators that are intended to overcome the MDR mechanisms in cancer cells and enhance the effect of chemotherapeutic agents.
The substrates produced are checked in particular for the following key aspects:
- Investigations into structure/activity relationships
- Molecular characterization of the MDR modulatory effect
- Specificity of transporter inhibition in vitro on expressing cells (MDR1, MRP)
- Competition studies in vitro and in situ on the perfused rat intestine with specific transporter substrates
Literatur: A. Hilgeroth, J. Molnár, E. de Clercq, Angew. Chem. Int. Ed. 41, 3623-3625 (2002);
M. Richter et al., Pharm. Res. 21, 1862-1866 (2004);
C. Coburger et al., J. Med. Chem. 51, 5871-5874 (2008);
D. Kreutzer et. al., Int. J. Mol. Sci. 22, 5098 (2021).
Project approvals
Approval of the EU project:
Bioanalytical Evaluation Studies of Novel Multidrug Resistance (MDR) Modulators to Reverse the MDR Phenomenon (1184256)
Approval of the DFG project:
Structure/efficacy evaluation of new "multidrug resistance" (MDR) modulators in vitro and in vivo (HI 687/5-3) as a joint project with the Clinical Pharmacy Working Group at the Institute of Pharmacy at the FU Berlin (Prof. Dr. Charlotte Kloft) and the Institute of Pathology at the Charité Berlin Hospital (Prof. Dr. Hermann Lage)
Approval of the DFG project:
Using novel active ingredients to develop new approaches to receptor-mediated tumor resistance (HI 687/10-1) as a joint project of the Medical Chemistry Working Group at the Institute of Pharmacy at the MLU (Prof. Dr. Wolfgang Sippl) and the Department of Clinical Pharmacy at the Institute of Pharmacy at the University of Greifswald (Prof. Dr. Christoph Ritter)