Potent and Selective RIPK1 Inhibitors Targeting Dual‐Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis

Abstract

Sepsis, characterized with high risk of life-threatening organ dysfunction, represents a major cause of health loss and the World Health Organization (WHO) labelled sepsis as the most urgent unmet medical need in 2017. The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we have synthesized a class of highly potent dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 (ZB-R-55) which is about 10-fold more potent than GSK2982772, and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model, suggesting that compound ZB-R-55 is a highly promising preclinical candidate.

Advances in RIPK1 kinase inhibitors

“…Benzodiazepine introduced alkynyl groups could be inserted into the ATP-binding pocket, and aromatic or aliphatic substitutions introduced into the alkynyl groups could bind to key residues in the pocket for additional hydrophobic or electrostatic interactions. Benzyl was installed in allosteric pockets and hydrophobic with the side chains of M67, L70, L129, S161 and H136 ( Yang et al, 2022 ). Triazoles form hydrogen bonds with main chains M67, V76 and L78 ( Yang et al, 2022 ).…”

“…Benzyl was installed in allosteric pockets and hydrophobic with the side chains of M67, L70, L129, S161 and H136 ( Yang et al, 2022 ). Triazoles form hydrogen bonds with main chains M67, V76 and L78 ( Yang et al, 2022 ). In addition, the amide carbonyl group and triazole form hydrogen bonds with the amide main chain NH of D156, and the benzoxazine part forms hydrophobic interactions with the side chains of M92 and L157 ( Yang et al, 2022 ).…”

“…Triazoles form hydrogen bonds with main chains M67, V76 and L78 ( Yang et al, 2022 ). In addition, the amide carbonyl group and triazole form hydrogen bonds with the amide main chain NH of D156, and the benzoxazine part forms hydrophobic interactions with the side chains of M92 and L157 ( Yang et al, 2022 ). Cypropyl acetylene is introduced on the alkyne group of 21 into the ATP binding pocket and produces additional hydrophobicity with S25, V31, G98 and L157.…”

“…ZB-R-55 has good in vitro anti-necrotizing droop and pharmacokinetic properties, which can be used to evaluate the efficacy of systemic inflammatory response syndrome (SIRS) model and lipopolysaccharide-induced sepsis model in vivo . Moreover, ZB-R-55 showed similar efficacy to glucocorticoid dexamethason in inhibiting cytokine storm ( Yang et al, 2022 ).…”

Cardiomyocyte death in sepsis: Mechanisms and regulation (Review)

“…Experimental studies have shown that peroxisome proliferator-activated receptor γ, a protein receptor with cardioprotective effects, decreases cardiac inflammation and alleviates sepsis-associated cardiomyopathy by inhibiting apoptosis and necroptosis ( 54 , 59 ). In vitro experiments have confirmed that heparan sulfate fragments (a class of danger/damage-associated molecular patterns) induce apoptosis in cardiomyocytes and RIP3-mediated necroptosis occurs over time, indicating that necroptosis is associated with sepsis-associated cardiomyopathy ( 56 , 60 ). Another study by Fu et al ( 61 ) suggested that necroptosis is activated by LPS in cardiomyocytes via the RIPK3/PGam5 signalling pathway.…”