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

Abstract

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 (K d,RIPK1 = 85 nM, K d,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.

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

“…In particular, RIPK1 is a foremost regulator of programmed cell necrosis (necroptosis), , which is closely related to the occurrence and development of various inflammatory and immune diseases . Notably, some RIPK-1 inhibitors are now progressing in the clinic for the treatment of inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis, as well as some neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). , …”

Insight from Linker Investigations: Discovery of a Novel Phenylbenzothiazole Necroptosis Inhibitor Targeting Receptor-Interacting Protein Kinase 1 (RIPK1) from a Phenoxybenzothiazole Compound with Dual RIPK1/3 Targeting Activity

“…To investigate whether compound 10 provides protection against RIPK1-driven inflammation in vivo, we examined its effect in a classical TNF-induced SIRS model. Referring to our previous in vivo studies on similar compounds ,,,, and better in vitro activity of compound 10 , three doses (1.25, 2.5, or 5 mg/kg) of 10 and intragastric administration were chosen. The compound was administered 2 h prior to the intravenous injection of mTNF-α.…”

“…To evaluate the antinecroptotic activity of target compounds, a chemiluminescence assay using TNF-α, Smac mimetic (SM-164), and a caspase inhibitor (z-VAD-FMK), abbreviated as TSZ, was conducted on human HT-29 cells. ,,− ,, The reference compound SZM-610, which contains the original ether linker (see Figure ), exhibits an antinecroptotic activity (EC 50 ) of 0.082 μM. , …”

Cell type‐specific molecular mechanisms and implications of necroptosis in inflammatory respiratory diseases

“…In addition to RIPK1 inhibitor Nec‐1/‐2, SZM‐1209, a benzothiazole derivative, also specifically targets RIPK1 against necroptosis 156 . SZM‐1209 shows a remarkable anti‐inflammatory effect as well as alleviates ALI through attenuating pulmonary edema and pathological damage 156 …”