SZM679 is an orally active, selective RIPK1 inhibitor displaying potent affinity with a dissociation constant (Kd) of 8.6 nM for RIPK1, while exhibiting minimal activity towards RIPK3, with a Kd of >5000 nM. It effectively counteracts tumor necrosis factor-induced systemic inflammation, reduces Tau hyperphosphorylation, diminishes neuroinflammation, and lowers RIPK1 phosphorylation in the hippocampus and cortex. SZM679 is utilized in Alzheimer’s disease (AD) research [1].

SZM679 exhibits anti-necrosis activity in necrotic L929 and HT-29 cells by inhibiting the RIPK1 pathway, with an EC50 value of 2 nM after exposure at concentrations of 0-10 μM for 24 hours. Additionally, SZM679 confers protection against necroptosis prompted by TNF-α, cycloheximide, and z-VAD-fmk (TCZ), demonstrating dose-dependent efficacy. In necrotic HT-29 cells, a 1 μM dose of SZM679 administered for 6 hours selectively suppresses RIPK1 expression without affecting RIPK3 or MLKL levels, and impedes necrosome assembly by blocking TSZ-triggered phosphorylation of RIPK1 [1].

SZM679 (10-40 mg/kg; i.p.; male C57BL/6 J mice with TNF-induced SIRS models) confers in vivo protection against necroptosis-specific, TNF-induced systemic inflammatory response syndrome (SIRS) [1]. Moreover, at a dosage of 1 mg/kg delivered intragastrically once daily for a week, SZM679 enhances cognitive function in STZ-induced Alzheimer's disease (AD) mice, mitigates brain structure damage, reduces AD biomarkers, and suppresses inflammatory cytokine expression, along with inhibiting RIPK1 phosphorylation in brain tissue, all without apparent toxicity [1].