From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors

Abstract

Necroptosis is a regulated caspase-independent form of necrotic cell death that results in an inflammatory phenotype. This process contributes profoundly to the pathophysiology of numerous neurodegenerative, cardiovascular, infectious, malignant, and inflammatory diseases. Receptor-interacting protein kinase 1 (RIPK1), RIPK3, and the mixed lineage kinase domain-like protein (MLKL) pseudokinase have been identified as the key components of necroptosis signaling and are the most promising targets for therapeutic intervention. Here, we review recent developments in the field of small-molecule inhibitors of necroptosis signaling, provide guidelines for their use as chemical probes to study necroptosis, and assess the therapeutic challenges and opportunities of such inhibitors in the treatment of a range of clinical indications.

Dopaminergic neuronal death via necroptosis in Parkinson's disease: A review of the literature

“…Nec‐1 and its derivatives named necrostatins were shown to inhibit RIPK1 in an ATP‐competitive manner, thus preventing its catalytic activity and rescuing cells from necroptosis. Unfortunately, Nec‐1 is unstable in vivo (t1/2 < 5 min in mouse liver microsomes) and toxic at concentrations >100 μM (Gardner et al, 2023; Teng et al, 2005). The derivative Nec‐1s is more potent and more stable in vivo (t1/2 ∼ 60 min in mouse liver microsomes) (Gardner et al, 2023).…”

“…Unfortunately, Nec‐1 is unstable in vivo (t1/2 < 5 min in mouse liver microsomes) and toxic at concentrations >100 μM (Gardner et al, 2023; Teng et al, 2005). The derivative Nec‐1s is more potent and more stable in vivo (t1/2 ∼ 60 min in mouse liver microsomes) (Gardner et al, 2023). Other necrostatins did not achieve the potency and subsequent widespread use of Nec‐1.…”

“…A study with DNL104 showed that CNS‐penetrant inhibition of RIPK1 phosphorylation may prevent brain inflammation and necroptosis in vivo (Grievink et al, 2020). Another RIPK1 inhibitor named R552 completed a phase I clinical trial and will enter phase II studies in autoimmune and inflammatory diseases (Gardner et al, 2023).…”

PROTACs Targeting MLKL Protect Cells from Necroptosis

“…38 Therefore, despite these critical early studies of MLKL, the development of new tools to complement established approaches is needed to help better understand the complex role of MLKL within disease and provide a starting point for drug discovery efforts. 39 PROteolysis TArgeting Chimeras (PROTACs) are a class of bifunctional molecules that can be used to target a protein of interest within a cell. Specifically, PROTACs effect a form of targeted protein degradation utilizing a catalytic, event-driven mechanism as opposed to the occupancy-driven mechanism of traditional small molecule inhibitors.…”

“…However, in some cases, RIPK3, but not MLKL knockout, abrogates symptoms or MLKL knockout exacerbates disease progression . Therefore, despite these critical early studies of MLKL, the development of new tools to complement established approaches is needed to help better understand the complex role of MLKL within disease and provide a starting point for drug discovery efforts …”