Laboratory of Molecular Pharmacology

We independently implement the full cycle of work: - computer modeling of candidate library interactions with MDM2 E3 ligase, - synthesis, isolation and purification of promising candidates, - creation of cellular test systems for identification of p53-mediated apoptosis, - testing of candidates on cell models, PCR and Western blotting. Publications: Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis, Cell Cycle, 10.1080/15384101.2018.1506664 Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction, Bioorganic & Medicinal Chemistry, 10.1016/j.bmc.2018.04.036 Proapoptotic modification of substituted isoindolinones as MDM2-p53 inhibitors, Bioorganic & Medicinal Chemistry, 10.1016/j.bmcl.2017.10.049 Simulation of MDM2 N terminal domain conformational lability in the presence of imidazoline based inhibitors of MDM2 p53 protein–protein interaction, Journal of Computer-Aided Molecular Design, 10.1007/s10822-019-00260-6

We independently implement the full cycle of work: - computer modeling of candidate library interactions with various AMPK sites, - synthesis, isolation and purification of promising candidates, - creation of cellular test systems to detect changes in AMPK activity, - testing of candidates on cell models, PCR and Western blotting. Publications: Activating Effect of 3-Benzylidene Oxindoles on AMPK: From Computer Simulation to High-Content Screening, ChemMedChem, 10.1002/cmdc.202000579 Is It Possible to Obtain a Product of the Desired Configuration from a Single Knoevenagel Condensation? Isomerization vs. Stereodefined Synthesis, Int. J. Mol. Sci., 10.3390/ijms241411339 Adaptation of the Mitsunobu Reaction for Facile Synthesis of Dorsomorphin-Based Library, Molecules, 10.3390/molecules30112258 Development of a Reproducible and Scalable Method for the Synthesis of Biologically Active Pyrazolo[1,5-a]pyrimidine Derivatives, Russian Journal of General Chemistry, 10.3390/ijms241411339

We independently implement the full cycle of work: - identification of potential sites of interaction of the transporter with inhibitors, - computer modeling of candidate library interactions with identified P-glycoprotein sites, - synthesis, isolation and purification of promising candidates, - creation of chemoresistant cell lines using a) cytostatic selection, b) selection of SP cells based on their ability to accumulate a P-glycoprotein substrate, c) 3D cultivation, - testing of candidates on cell models, PCR and Western blotting. Publications: New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics, Biomedicines, 10.3390/biomedicines12030547 Mdm2 inhibitors as a platform for the design of P-glycoprotein inhibitors, Bioorg Med Chem Lett, 10.1016/j.bmcl.2020.127424 Implication of ABC transporters in non-proliferative diseases, Bioorg Med Chem Lett, 10.1016/j.bmcl.2020.127424 Establishment of drug-resistant cell lines under the treatment with chemicals acting through different mechanisms, Chemico-Biological Interactions, 10.1016/j.cbi.2021.109510

Parallel work is underway to create MDM2-rectracting PROTACs aimed at deactivating P-glycoprotein and autoubiquitinylation followed by MDM2 proteolysis. Protein targets have been studied in detail during the implementation of other projects. The synthesis methods were partially developed during the work on the creation of MDM2 inhibitors. Synthetic work is currently underway to assemble full-size PROTACs for subsequent testing. Publications: PROTAC-attractive site as a new target for suppressing P-glycoprotein activity, Archives of Biochemistry and Biophysics, 10.1016/j.abb.2024.110258 Ubiquitin recruiting chimera: more than just a PROTAC, Biology Direct 10.1186/s13062-024-00497-8