DESIGN OF CATALYTIC INHIBITORS OF TOPOISOMERASE II
To increase the safety profile of this proven chemotherapy approach and discover effective chemotherapeutic agents that inhibit the human DNA topoisomerase IIα , we take advantage of an alternative inhibition mechanism of its complex catalytic cycle and develop catalytic inhibitors that bind to its ATP pocket thus avoiding the DNA damage and lowering the chances of side effects associated with topo II poisons.
In our research, we take advantage of the drug discovery cycle paradigm. The starting point for our design efforts is the available structural information about the conformation of the ATPase domain. We use computational design methods such as molecular docking calculations and various pharmacophore modeling approaches. We complement these data with molecular simulations. The compounds we design are first tested in various biochemical assays and then characterized in biophysical experiments (e.g. surface plasmon resonance (SPR) and microscale thermophoresis (MST)) using only the ATPase domain. In collaboration with experimental partners, we are also determining the citotoxicity of the compounds on various cancer cell lines to evaluate the preclinical anticancer potential of these compounds. The data we obtain feed the next itation of the described experiments.
Schematic representation of our design process for new topoisomrase IIα catalytic inhibitors identification.
SELECTED PUBLICATIONS
HERLAH Barbara, JANEŽIČ Matej, OGRIS Iza, GOLIČ GRDADOLNIK Simona, KOLOŠA Katja, ŽABKAR Sonja, ŽEGURA Bojana, PERDIH Andrej. Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα: Dynophore-derived discovery. Biomedicine & Pharmacotherapy (175), 2024, 116676. Full text
JANEŽIČ, Matej, VALJAVEC, Katja, BERGANT LOBODA, Kaja, HERLAH, Barbara, OGRIS, Iza, KOZOROG, Mirijam, PODOBNIK, Marjetka, GOLIČ GRDADOLNIK, Simona, WOLBER, Gerhard, PERDIH, Andrej. Dynophore-based approach in virtual screening : a case of human DNA topoisomerase IIα. International journal of molecular sciences. 2021, 22(24), 13474. Full text
BERGANT LOBODA, Kaja, VALJAVEC, Katja, ŠTAMPAR, Martina, WOLBER, Gerhard, ŽEGURA, Bojana, FILIPIČ, Metka, SOLLNER DOLENC, Marija, PERDIH, Andrej. Design and synthesis of 3,5-substituted 1,2,4-oxadiazoles as catalytic inhibitors of human DNA topoisomerase IIα. Bioorganic chemistry. 2020, 99, 103828. Link
BERGANT Kaja, JANEŽIČ Matej, VALJAVEC Katja, SOSIČ Izidor, PAJK Stane, ŠTAMBAR Martina, ŽEGURA Bojana, GOBEC Stanislav, FILIPIČ Metka, PERDIH Aandrej. Structure-guided optimization of 4,6-substituted-1,3,5-triazin-2(1H)-ones as catalytic inhibitors of human DNA topoisomerase IIα, European Journal of Medicinal Chemistry, 2019, 175, 330-348. Link