PhD defence J. (Jianqiu) Zhang

Molecular approaches to modulate enzymatic activity of proteins involved in pathways of cell death

In this thesis, we explored the development of small molecules that can influence cell death by targeting three very different proteins: 15-lipoxygenase-1 (15-LOX-1), macrophage migration inhibitory factor (MIF) and histone deacetylases (HDACs). The developed 15-LOX-1 inhibitors inhibited RSL3-induced lipid peroxidation and protected cells from RSL3-induced cell death. Furthermore, the developed MIF-directed small molecule modulators enhanced ferroptosis via a putative MIF-BRCA1-RAD51 axis in HR, which caused resistance to ferroptosis. Finally, the developed HDAC8 PROTACs potently inhibited proliferation of various cancer cell lines by triggering various antiproliferative mechanisms such as cell cycle arrest, apoptosis, and lipid peroxidation. This enabled a deeper understanding of the regulation of cell death and the possibilities to interfere with these processes by small molecule modulators. Ultimately, this will provide new possibilities for therapeutic intervention.