Using computer-aided drug design we discovered a new class of substituted bithiazoles, acting as catalytic inhibitors of human DNA topoisomerase II?. Through extensive biochemical evaluation we then determined the mechanism of action and level of activity. Bithiazoles bind to the topo II? ATPase domain and inhibit the enzyme via an ATP competitive mechanism. In vitro, the investigated compounds inhibit the human topoisomerase II? in a superior fashion compared to some of the clinical topo II poisons. On a cellular level they exhibit cytotoxicity comparable to topo II agents used in chemotherapy but show no induction of DNA double-strand breaks (DBS). Additional assays reveal they reduce the cell proliferation and stop the cell cycle mainly in the G1 phase, all in accordance with a mechanism of action distinct from topo II poisons. Due to the significant potential of this chemical class, we have filed international patent applications (first LU and then EP application) for this class of compounds as promising new chemotherapeutics with comparable anticancer activity as clinically useful topoisomerase poisons. The compounds have a different topoisomerase II? inhibition mechanism and thus may also posses a safer therapeutic profile. Furthermore, these molecules are also useful in combination with some of the established anti-cancer agents to enhance the existing chemotherapeutic treatments.
F.32 International patent
COBISS.SI-ID: 40284421In the scope of the course Structures of Biological molecules, part of the undergraduate curriculum of Bioinformatics at the Faculty of Mathematics, Natural Sciences and Information Technologies (FAMNIT), University of Primorska, a new textbook for this course was published by two members of the P1-0012 research program (dr. Andrej Perdih, and young reserach Alja Prah).
D.10 Educational activities
COBISS.SI-ID: 28974595As part of the exhibition activity at the National Institute of Chemistry, which has a tradition since the late 1970s, a member of the program group P1-0012 doc. dr. Andrej Perdih together with dr. Damjan Makuc and curator Jiri Kocica prepared an exhibition of photographs by both authors. An small exhibition booklet was also published accompanying the exhibition.
F.28 Organising an exhibition
COBISS.SI-ID: 38449155A member of the program group presented our research achievements on the origin of enzyme catalysis and the activity of MAO enzymes at an internatioal scientific conference.
B.04 Guest lecture
COBISS.SI-ID: 6682906A member of the program group presented in the renowned television show research requiring the use of high computational power to address cutting-edge issues in science. He also highlighted the achievements of our program group, mainly elucidation of the driving force behind enzyme catalysis.
B.06 Other
COBISS.SI-ID: 6794266