RIPK1 (Receptor-interacting serine/threonine-protein kinase 1), a 76-kDa protein, is an essential mediator of cell death and inflammation. This protein has a N-terminal kinase domain, a C-terminal death domain, and an intermediate domain with an RHIM (receptor-interacting protein homotypic interacting motif). RIPK1 is important for regulating pro-survival NF-κB signaling. In the central nervous system (CNS), RIPK1 exists in all major cell types. An experiment in vitro proved that RIPK1 kinase activation leads to an inflammatory CNS environment that accelerated multiple sclerosis progression. The activation of RIPK1 kinase has been found in pathological samples of autoimmune and neurodegenerative conditions. And the inhibition of RIPK1 has shown efficacy in these diseases, such as Alzheimer’s disease (AD). Therefore, RIPK1 is a key target for the treatment of RIPK1-related diseases.

SZM679 is an orally active and selective RIPK1 inhibitor, possessing the potential to treat Alzheimer’s disease.

Firstly, SZM679 shows a high affinity for RIPK1 with a K_d value of 8.6 nM. Furthermore, it decreases the Tau hyperphosphorylation, neuroinflammation, and the RIPK1 phosphorylation level in the hippocampus and cortex.

Secondly, the experiment in vitro proved that this inhibitor has an anti-necrosis activity by Inhibiting the RIPK1 pathway with an EC₅₀ value of 2 nM. SZM679 also protected against TNF-α, cycloheximide, and z-VAD-fmk (TCZ)-induced necroptosis. Moreover, it blocks necrosome formation by inhibiting TSZ-induced phosphorylation of RIPK1.

Thirdly, SZM679 shows oral activity in animal models. It protected against necroptosis-specific TNF-induced systemic inflammatory response syndrome (SIRS) mice model. In addition, in Streptozocin-induced AD mice, SZM679 (1 mg/kg, i.g., once daily for 7 days) improves cognitive function including anxiety, behavior, as well as exploratory ability, learning, and memory ability. Besides, it also rescues brain structure damage with no obvious toxicity and decreases AD biomarkers and decreases the expression levels of inflammatory cytokines in the brain tissues of AD mice.

In conclusion, SZM679 is a highly effective RIPK1 inhibitor, that reverses the tumor necrosis factor-induced systemic inflammatory response. SZM679 has the potential to treat Alzheimer’s disease.

References:

1. Zelic M, et al. Cell Rep. 2021 May 11;35(6):109112.

2. Mifflin L, et al. Nat Rev Drug Discov. 2020 Aug;19(8):553-571.