SZM-1209 is an Orally Active RIPK1 Inhibitor with Anti-SIRS and Anti-ALI Effects

Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases. There are seven members of the RIPK family, RIPK1-7. RIP kinases are cellular signaling molecules that are critical for homeostatic signaling in both communicable and non-communicable disease processes. RIPK1, RIPK2, RIPK3 and RIPK7 have emerged as key mediators of intracellular signal transduction. Thus it is essential for the early control of many diverse pathogenic organisms.

RIPK1 has a N-terminal kinase domain, a C-terminal death domain and an intermediate domain with a RHIM (RIP homotypic interacting motif) that can bind to other RHIM-containing proteins. RIPK1 is a master regulator of the cellular decision between pro-survival NF-κB signalling and death in response to a broad set of inflammatory and pro-death stimuli in human diseases. Meanwhile, RIPK1 kinase activation has been demonstrated in post-mortem human pathological samples of autoimmune and neurodegenerative conditions. Thus, Potential applications of RIPK1 inhibitors for the treatment of monogenic and polygenic autoimmune, inflammatory, neurodegenerative, ischaemic and acute conditions, such as sepsis, are emerging.

SZM-1209 is a potent, selective and orally active inhibitor of RIPK1.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are serious and devastating pulmonary manifestations of acute systemic inflammation with high morbidity and mortality worldwide. RIPK1, which contributes to necroptosis and inflammation, is confirmed to be a promising strategy for the treatment of ALI. SZM-1209 is an orally active, potent and specific RIPK1 inhibitor. SZM-1209 specifically targets RIPK1 instead of RIPK3, and exhibited high anti-necroptotic activity. Moreover, in a mTNF-α-induced systemic inflammatory response syndrome (SIRS) model, SZM-1209 could completely reverse mouse deaths with significant anti-inflammatory effects. Furthermore, in a NNK short-term intratracheal exposure-induced ALI model, SZM-1209 significantly alleviated ALI by reducing pulmonary edema and pathological damage.

All in all, SZM-1209 is an orally active, potent and specific RIPK1 inhibitor that has the potential for the research of ALI/ARDS.


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

[2] Zhang X, et, al. J Med Chem. 2023 Apr 13;66(7):5261-5278.