Abstract
Different types of cells deaths play a key role in the pathogenesis of many different diseases such as neurodegenerative disorders, multiorgan injury and cancer. In addition to the well-known apoptosis, novel forms of regulated necrosis have been discovered. Particularly, ferroptosis and necroptosis have emerged as new types of non-apoptotic form of cell death of which ferroptosis is involved in reactive oxygen species (ROS) formation. ROS accumulation promotes damage in different organs and tissues, and could potentially start the release of pro-inflammatory cytokines leading to inflammation and cell membrane disruption.
The aim of the project is twofold: 1) the design and synthesis of novel radical trapping agents (RTAs) to hinder the accumulation of lipid hydroperoxides linked with ferroptosis and 2) the design and synthesis of novel receptor interacting serine/threonine kinase 1 (RIPK1) inhibitors to prevent necroptosis.
Ferroptosis project: recently, in the MedChem group at the university of Antwerp (UAMC), two novel compounds, namely UAMC-0003203 and UAMC-0003206 have been published and patented as new RTAs able to block the lipid hydroperoxide formation. With higher potency, stability and solubility compared to the well-known benchmark compound Ferrostatin 1, the novel lead compounds can have a therapeutic potential in relevant ferroptosis-driven disease models. A novel library of ferroptosis inhibitors has been successfully synthetized aiming to improve potency, selectivity and ADME properties of the reference compounds. A new ferroptosis in vitro model will be developed in collaboration with prof. Dr. Tom Vanden Berghe to test the library of ferroptosis inhibitors.
Necroptosis project: in the necroptosis pathway RIPK1 plays a pivotal role. RIPK1 is a key mediator of inflammation, which is considered the core-mechanism of many pathologies. Thus, RIPK1 is considered a an emerging kinase target in the field of regulated necrosis. A library of Tozasertib analogues, able to selectively inhibit RIPK1, has been synthetized by UAMC. UAMC-0003063 and UAMC-0003064 are the most potent compounds of the library and the improvement of their potency, selectivity and ADME profile was the initial idea of the project. Recently, it was discovered that the GlaxoSmithKline compound GSK2656157, known as a Protein kinase R (PKR)-like ER kinase (PERK) inhibitor, was a potent and selective inhibitor for RIPK1. We therefor studied the differences between the two kinase enzymes PERK and RIPK1 and how the molecule interacts with the active binding site. The development of selective inhibitors is a challenge in the family of protein kinases due to their strong similarities in the ATP binding pocket. Particular attention is therefore given to the interaction with the allosteric pocket, also known as selectivity pocket. Based on a published RIPK1 crystal structure it was possible to further investigate the structural differences between PERK and RIPK1. The synthesis of a novel library of more selective RIPK1 analogues is now being finalized. In vitro tests will be performed to assess the potency and the binding affinity of the novel analogues.
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