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Updated: Aug 1, 2025
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors
Camilla Scarpellini1, Sophie Valembois1, Kenneth Goossens1
1Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
Abstract:
Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1) emerged as an important driver of inflammation and, consequently, inflammatory pathologies. The enzymatic activity of RIPK1 is known to indirectly promote inflammation by triggering cell death, in the form of apoptosis, necroptosis and pyroptosis. Small molecule Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors have therefore recently entered clinical trials for the treatment of a subset of inflammatory pathologies. We previously identified GSK2656157 (GSK'157), a supposedly specific inhibitor of protein kinase R (PKR)-like ER kinase (PERK), as a much more potent type II Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitor. We now performed further structural optimisation on the GSK'157 scaffold in order to develop a novel class of more selective Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors. Based on a structure-activity relationship (SAR) reported in the literature, we anticipated that introducing a substituent on the para-position of the pyridinyl ring would decrease the interaction with PERK. Herein, we report a series of novel GSK'157 analogues with different para-substituents with increased selectivity for Receptor-Interacting serine/threonine-Protein Kinase 1. The optimisation led to UAMC-3861 as the best compound of this series in terms of activity and selectivity for Receptor-Interacting serine/threonine-Protein Kinase 1 over PERK. The most selective compounds were screened in vitro for their ability to inhibit RIPK1-dependent apoptosis and necroptosis. With this work, we successfully synthesised a novel series of potent and selective type II Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors based on the GSK'157 scaffold.
Insights
Researchers developed new, selective inhibitors for Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1), a key driver of inflammation. These novel compounds, based on the GSK'157 scaffold, show improved selectivity over PERK and effectively inhibit RIPK1-dependent cell death pathways.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Immunology
Background:
- Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1) is a critical mediator of inflammatory responses and associated pathologies.
- RIPK1 activity drives inflammation by inducing cell death pathways, including apoptosis, necroptosis, and pyroptosis.
- Small molecule RIPK1 inhibitors are under clinical investigation for treating inflammatory diseases.
Purpose of the Study:
- To develop novel, highly selective inhibitors of Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1) based on the GSK2656157 (GSK'157) scaffold.
- To enhance the selectivity of GSK'157 for RIPK1 over protein kinase R (PKR)-like ER kinase (PERK).
- To synthesize and evaluate novel GSK'157 analogues with improved RIPK1 inhibitory activity and selectivity.
Main Methods:
- Structure-activity relationship (SAR) studies guided the modification of the GSK'157 scaffold.
- Introduction of para-substituents on the pyridinyl ring of GSK'157 analogues to modulate PERK interaction.
- In vitro screening of synthesized compounds for RIPK1 inhibitory activity, selectivity over PERK, and inhibition of RIPK1-dependent apoptosis and necroptosis.
Main Results:
- A series of novel GSK'157 analogues with varying para-substituents were synthesized.
- Optimized analogues demonstrated increased selectivity for RIPK1 compared to PERK.
- Compound UAMC-3861 emerged as the lead compound, exhibiting potent activity and high selectivity for RIPK1.
- The most selective compounds effectively inhibited RIPK1-dependent apoptosis and necroptosis in vitro.
Conclusions:
- The study successfully generated a new class of potent and selective type II RIPK1 inhibitors.
- The optimized compounds, derived from the GSK'157 scaffold, offer potential therapeutic agents for inflammatory diseases.
- These findings provide valuable insights into the development of targeted RIPK1-based therapies.
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