Screening and Lead Optimization of Necroptosis Inhibitors

About:
Necroptosis is a type of regulated cell death that plays critical roles in health and disease. Most necroptosis pathways activate receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and 3 (RIPK3), causing the phosphorylation of mixed lineage kinase domain like pseudokinase (MLKL). The activation of MLKL leads to plasma membrane permeabilization and a subsequent release of cellular content, leading to inflammatory responses and contributing to the pathogenesis of chronic inflammatory diseases.
A necroptosis inhibition high-throughput cell-based screening was carried out to identify new compounds with antinecroptotic activity. Several hit compounds with high potency against RIPK1 and a dissimilar scaffold from the known necroptosis inhibitors were identified.1 The scaffold of these hit compounds was explored in hit-to-lead optimization campaigns. Herein we report the SAR studies performed to select lead compounds endowed RIPK1 and necroptosis inhibition potency, as well as with in vivo efficacy in a model of TNF-induced systemic inflammatory response syndrome (SIRS).  

1.    H. Brito, V. Marques, M.B. Afonso, D. G. Brown, U. Börjesson, N. Selmi, D.M. Smith, I.O. Roberts, M. Fitzek, N. Aniceto, R.C. Guedes, R. Moreira, C.M.P. Rodrigues. Phenotypic high-throughput screening platform identifies novel chemotypes for necroptosis inhibition. Cell Death Discov 2020, doi: 10.1038/s41420-020-0240-0.
 

CV highlights and research lines:
Rui Moreira is a Full Professor of Medicinal Chemistry medicinal chemist by training, with a PhD degree in Medicinal Chemistry from the University of Lisbon. He is a Full Professor in 2006. From 2010 to 2013, Rui Moreira was the coordinator of the Research Institute for Medicines (iMed.ULisboa). Since 2022 he has been the president of the Department of Pharmaceutical Sciences and Medicines at FFUL. He is a co-founder and board member of PT-OPENSCREEN, a national chemical biology and genetics infrastructure that recently joined the ERIC EU-OPENSCREEN (EU-OS). Rui Moreira is the leader of iMed.ULisboa’s Medicinal Chemistry Partner Site at EU-OS since 2022. He was the President of of the European Federation for Medicinal Chemistry and Chemical Biology (EFMC) from 2021 to 2023, currently its Past President. 
Rui Moreira’s research interests are focused on chemistry-centric approaches to address key medical needs. He has developed several endoperoxide-based tools for ferrous iron-based pharmacology to tackle malaria and cancer. He has made substantial contributions to the design of covalent inhibitors targeting cysteine and serine hydrolases, and to translate them into activity-based probes (ABPs) for proteome profiling and target deconvolution. He is also actively involved in identifying novel chemotypes targeting necroptosis, a programmed form of necrosis, and its key effectors. He published 180 papers, including in high-impact journals such as J Am Chem Soc, Angew Chem Int Ed, Proc Natl Acad Sci and J Med Chem. He supervised and mentored >50 PhD/MSc students and postdocs. He has successfully established international research programs on medicinal chemistry for malaria and necroptosis that attracted support from the Medicines for Malaria Venture (MMV) and AstraZeneca (AZ).
 

Host PI: Mabel Loza, Pharmacology Applied to Drug Discovery (BioFarma) Group, CiMUS.

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