Abstract
Reduced delivery of the drug into the cell due to increased activity of specific transporter P-glycoprotein is one of the main mechanisms of drug resistance development. The inhibition of the activity of such a pump increases the intracellular concentration of the drug and contributes to cancer cell death. The combination of factors that allows one to overcome genetically determined resistance and to trigger apoptosis in one small molecule compound can lead to the development of new type of drugs for personalized therapy of chemoresistant tumors. In the course of work on optimization of MDM2 inhibitors based on indolinones and isoindolinones, we found fragments of the structure that can be modified with minimal risk of a decrease in the target activity. The combination of in silico and in vitro methods allowed the selection of compounds that showed strong binding to the target sites of P-glycoprotein and MDM2, and a good combination of solubility - membrane-active properties, which implies high bioavailability of the drug.
Highlights
Multiple drug resistance (MDR) of cancer cells, when the tumor is insusceptible to a wide range of drugs with a different mechanism of action, is an important issue in the chemotherapy of proliferative diseases
Pgp is expressed in cells whose function is related to detoxification and elimination of xenobiotics, in particular, in intestinal epithelium, liver, immunocompetent cells, excessive activity of the efflux mechanism leads to the formation of multidrug resistance of cancer cells [3]
In the course of work on optimization of MDM2 inhibitors based on indolinones and isoindolinones [19,20,21], we found fragments of the structure that can be modified with minimal risk of a decrease in the target activity, i.e. ability to inhibit the formation of the complex MDM2-p53
Summary
Multiple drug resistance (MDR) of cancer cells, when the tumor is insusceptible to a wide range of drugs with a different mechanism of action, is an important issue in the chemotherapy of proliferative diseases. The prevention of secondary drug resistance and overcoming chemoresistance of primary tumors is an important issue of modern oncology, which can be solved by developing new drugs for personalized therapy.
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