From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors

Camilla Scarpellini; Sophie Valembois; Kenneth Goossens; Mike Vadi; Caroline Lanthier; Greta Klejborowska; Pieter Van Der Veken; Hans De Winter; Mathieu J M Bertrand; Koen Augustyns

doi:10.3389/fchem.2023.1160164

From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors

Front Chem. 2023 Apr 7:11:1160164. doi: 10.3389/fchem.2023.1160164. eCollection 2023.

Authors

Affiliations

¹ Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
² Vlaams Instituut voor Biotechnologie (VIB) Center for Inflammation Research, Ghent, Belgium.
³ Laboratory Cell Death and Inflammation, Department of Biomedical Molecular Biology, Ghent University, Ghent, 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.

Keywords: PERK (PKR-like endoplasmic reticulum kinase); RIPK1 inhibitor; inflammation; necroptosis; regulated cell death; type II kinase inhibitor.

Grants and funding

This work was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 765608. This research was also funded by the University of Antwerp, BOF DOCPRO grant no.44874 and FWO-EOS Research project no. 36579. Research in the group of MB is financially supported by the Vlaams Instituut voor Biotechnologie (VIB), by Ghent University (iBOF ATLANTIS), by grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) (G035320N, G044518N, EOS G0G6618N, EOS G0I5722N) and from the Flemish Government (Methusalem BOF09/01M00709 and BOF16/MET_V/007 - attributed to P. Vandenabeele).