Discovery of necroptosis and ferroptosis inhibitors with potential applications in pathologies associated with regulated necrosis
18 september 2018
UAntwerpen, Campus Drie Eiken, Gebouw O, Auditorium O1 - Universiteitsplein 1 - 2610 Antwerpen (Wilrijk) (route: UAntwerpen, Campus Drie Eiken
16 - 18 uur
Koen Augustyns - Hans De Winter
Doctoraatsverdediging Lars Devisscher - Departement Farmaceutische Wetenschappen
Historically, cell death has been divided between forms that are regulated and forms that occur accidentally. Apoptosis is the most extensively studied form of regulated cell death and is considered indispensable during aging and development. Necrosis was originally described as the non-regulated demise of cells which were faced with extreme physicochemical insults. In recent years, several forms of necrosis have been described and their underlying regulatory molecular mechanisms have been elucidated.
This PhD focuses on the design and synthesis of novel inhibitors of two forms of regulated necrosis, namely necroptosis and ferroptosis. These molecules can be used in various in vitro and in vivo settings to investigate the biochemical processes and pharmacological targetability of necroptosis and ferroptosis.
Necroptosis is dependent on the activity of Receptor Interacting Protein Kinase 1 (RIPK1) and the closely related RIPK3. Early findings showed that the pharmacological targeting of RIPK1 and RIPK3 by small molecules or genetic modification can result in the inhibition of necroptosis. The most well-known group of necroptosis inhibitors, the necrostatins, act primarily through the allosteric inhibition of RIPK1. Even though these molecules are potent and selective, their non-ideal pharmacokinetic properties prevent their efficient use in in vivo settings. Most necroptosis inhibitors target the RIPK enzymes by exploiting the inactive conformation of these enzymes which classifies them as either type II or type III kinase inhibitors. Tozasertib was recently identified as a molecule that showed great affinity towards RIPK1 suggesting that it might be able to act as a necroptosis inhibitor. Interestingly, tozasertib binds to the active conformation of a protein kinase and can thus be classified as a type I kinase inhibitor. As such, the first aim of this PhD is the design and synthesis of tozasertib analogues which can be used as novel necroptosis inhibitors that target the active conformation of RIPK1.
Ferroptosis was recently described as an iron-dependent form of regulated necrosis which is caused by the accumulation of toxic lipid peroxides. Ferrostatin-1 (Fer-1) was identified as a potent ferroptosis inhibitor but the actual in vivo applications of Fer-1 are limited due to the presence of a labile ester moiety. During this PhD research, the second aim was to design and synthesize Fer-1 analogues with improved stability so that they can be used to investigate ferroptosis in vivo. Several analogues displayed improved stability and potency which allows them to serve as ideal tool compounds to investigate ferroptosis in vivo.