Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway

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. Currently,
there are no specific effective treatments for ALI/ARDS. RIPK1, which
contributes to necroptosis and inflammation, is confirmed to be a
promising strategy for the treatment of ALI. Herein, 23 benzothiazole
derivatives were designed to specifically target RIPK1, and SZM-1209 showed high anti-necroptotic activity (EC50 = 22.4 nM) and kinase selectivity on RIPK1 over RIPK3 (Kd,RIPK1 = 85 nM, Kd,RIPK3 >
10,000 nM). 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. Collectively, activities of SZM-1209 against RIPK1, necroptosis, SIRS, and ALI warranted further investigation
of optimized benzothiazoles as promising lead structures against ALI-related
diseases.