Mdm2 inhibitors as a platform for the design of P-glycoprotein inhibitors
| Autor: | Angelina Romanova, Vyacheslav G. Tribulovich, Svetlana V. Vorona, Aleksandra Sagaidak, Daria S. Novikova, Tatyana A. Grigoreva |
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| Rok vydání: | 2020 |
| Předmět: |
Drug
Isatin Models Molecular Combination therapy media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Drug resistance Pharmacology 01 natural sciences Biochemistry Piperazines Structure-Activity Relationship Drug Discovery Humans Computer Simulation ATP Binding Cassette Transporter Subfamily B Member 1 Enzyme Inhibitors Molecular Biology P-glycoprotein media_common biology 010405 organic chemistry Chemistry Organic Chemistry Rational design Imidazoles Biological activity Proto-Oncogene Proteins c-mdm2 Drug Resistance Multiple 0104 chemical sciences 010404 medicinal & biomolecular chemistry biology.protein Quinolines Molecular Medicine Mdm2 Efflux Drug Screening Assays Antitumor Heterocyclic Compounds 3-Ring Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry letters. 30(18) |
| ISSN: | 1464-3405 |
| Popis: | Chemoresistance is thought to be the cause of low treatment efficacy and mortality in more than 90% of patients with advanced cancer. The activation of drug efflux by P-glycoprotein is the key mechanism of resistance. All known P-gp inhibitors are used only in the combination therapy. We propose a new approach based on the multitarget rational design of drugs, which possess both the antitumor and efflux pump inhibitory activity. In this work, the principle possibility of combining the ability to inhibit P-gp and p53-Mdm2 protein-protein interaction in one structure is considered. The biological activity of a number of known and newly synthesized compounds was evaluated using cell lines with different p53 status. The possibility of using computer modeling for the search for P-glycoprotein inhibitors among Mdm2 inhibitors was analyzed; P-gp interaction site and binding modes of substrates and inhibitors were identified. The results obtained in cells that have the native balance of drug resistance and sensitivity showed the ability of the cells to both actively throw out xenobiotics and to lose this ability using P-gp inhibitors. The data obtained indicate that Mdm2 inhibitors are a promising platform for the development of multitarget drugs that can overcome tumor resistance by inhibiting the P-glycoprotein activity. |
| Databáze: | OpenAIRE |
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