Development of PROTACs for pharmacologically important proteins The degradation of specific protein targets using heterobifunctional molecules (such as PROTACs) has been rapidly adopted as a tool for biological research and as a potential modality for the discovery of new drugs. Obtaining FEBS Scholarship in 2018 enabled me to perform a research stay in the group of prof. dr. Michael Gütschow (an expert in the field of PROTACs development) at the University of Bonn. The grant was focused on the design and synthesis of PROTAC precursors for the incorporation into degraders for BCL-2 family of enzymes (Steinebach, C.; Sosič, I. et al. MedChemComm 2019, 10, 1037-1041). After returning to the Faculty of Pharmacy, University of Ljubljana, I continue with research efforts in this field with the main aim to develop degraders of BCL-2 and BAX. In addition, I am maintaining a strong collaboration with the research groups from the University of Bonn, where we focus on other proteins involved in malignant diseases (e.g. CDK4 and CDK6; manuscript submitted to Chem. Sci. January 2020). Mechanism-based inhibitors of the immunoproteasome In the field of (immuno)proteasome, my goal is to develop novel inhibitors and molecular probes targeting these enzymatic machineries to further define their biochemical roles and additionally uncover their potential as therapeutic targets. The intensive, innovative and focused work culminated in a granted patent in the European Union in 2018, as well as a breakthrough publication in Angewandte Chemie International Edition in 2016 (Sosič, I. et al. Angew. Chem. Int. Ed. 2016, 55, 5745-5748). In addition, our research group obtained funding from ARRS to develop non-peptidic inhibitors by using fragment-based drug design in collaboration with the group of Dr. György Miklós Keserű from the Hungarian Academy of Sciences. Inhibitors of bacterial cell wall biosynthesis Numerous enzymes that are involved in peptidoglycan biosynthesis represent potential targets for the development of new antibacterial agents. The research work is oriented mainly on Mur enzymes (MurA to MurF), DdlB, and Penicilin-Binding Proteins. The aim is to improve inhibitory activities, as well as physico-chemical and pharmacokinetic properties of new compounds. Using modern drug design techniques enables optimization of compounds in an iterative manner combining computational design, synthesis of compounds, biochemical evaluation, microbiological assays, and preliminary pharmacokinetic and toxicological evaluation Design, synthesis, and preclinical evaluation of cathepsin B inhibitors Within cathepsin B, the aim of our research group is to develop advanced lead compounds that can be progressed into clinical studies. We are focusing on non-peptidic inhibitors based on the 8-hydroxyquinoline scaffold. A lot of data was generated through the Postdoctoral project, funded by ARRS (2016-2017), with the title Optimization of nitroxoline-based inhibitors of cathepsin B as potential drugs for the treatment of cancer. We were successful in preparing non-peptidic compounds with promising pre-clinical results in terms of cathepsin B inhibition and anti-tumour characteristics both in vitro and in vivo.