Protein degraders for targeting galectin-8

Objectif

In the PROTAG-8 project, we aim to target galectin-8 by protein degradation using proteolysis targeting chimeras or shortly, PROTACs. Galectin-8 is a galactoside-binding lectin that exists as a soluble intracellular and extracellular receptor, with an extensive exchange between the membrane-bound and cytosolic forms. Its inhibitors are potential new anticancer drugs, but the affinity of classical galectin-8 inhibitors is in the low micromolar range, hardly sufficient for their use as drug molecules. The overarching aim of PROTAG-8 is to explore whether the PROTAC method can be implemented for galectin-8 and to answer the question of whether PROTACs offer advantages over classical selective galectin-8 ligands. Since PROTACs need only bind their targets with high selectivity and with an affinity high enough to stabilize the ternary complex between the protein of interest and the E3 ligase, the affinity in the micromolar range could be sufficient for their activity, unlike conventional ligands. The current state-of-the-art in the development of PROTACs focuses only on intracellular proteins, but galectin-8 exists as both an intracellular and extracellular protein. Based on this fact, we want to find out whether such a receptor, which occurs both in the cytosol and in the extracellular matrix, can be effectively targeted with PROTACS and its activity modulated. This scientific question will be tackled by a highly-qualified PhD Nives Hribernik with international experience in glycochemistry, medicinal chemistry and chemical biology, and is expected to be an excellent springboard to her independent scientific career. The project proposal includes renowned principal investigators from two academic institutions: Prof. Dr. Marko Anderluh from the University of Ljubljana (Slovenia), and Prof. Dr. Ulf Nilsson and Prof. Derek Logan from Lund University (Sweden), giving the PROTAG-8 international and interdisciplinary background.