Structure-based optimizations of a necroptosis inhibitor (SZM594) as novel protective agents of acute lung injury

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Directly inhibiting the Keap1–Nrf2 protein–protein interaction has been investigated as a promising strategy to activate Nrf2 for anti-inflammation. We previously reported a naphthalensulfonamide Keap1–Nrf2 inhibitor NXPZ-2, but have not determined the exact binding mode with Keap1. This symmetric naphthalenesulfonamide compound has relatively low solubility. Herein, we first determined a crystal complex (resolution: 2.3 Å) of human Keap1 Kelch domain with NXPZ-2. Further optimizations on the solvent exposed region obtained asymmetric naphthalenesulfonamides and three crystal structures of Keap1 in complex with designed compounds. Among them, the asymmetric piperazinyl-naphthalenesulfonamide 6k with better aqueous solubility showed the best K D2 value of 0.21 μM to block the interaction. The productions of ROS and NO and the expression of TNF-α were inhibited by 6k in the in vitro model. This compound could relieve inflammations by significantly increasing the Nrf2 nuclear translocation in the LPS-induced ALI model with promising pharmacokinetic properties.

Section: Resultsmentioning

confidence: 99%

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

Liu

Hou

et al. 2022

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“…Our knowledge-based SAR studies showed that the right terminal benzyl group of SZM594 was critical to RIPK3 selectivity and the benzothiazole ring was favorable to increase RIPK1 selectivity. − First, we generated a predicted structural binding insight of SZM594 with RIPK1 for our selectivity improvement. It is revealed that SZM594 with no substitution on the benzothiazole ring was flexible for the phenylether bond in the RIPK1 kinase domain nearby the “Asp-Leu-Gly (DLG)” gatekeeper, which is different from the “Asp-Phe-Gly (DFG)” of RIPK3.…”

Section: Resultsmentioning

confidence: 99%

“…Our data have clearly indicated that the selective inhibition of RIPK1 may account for decreasing inflammatory cytokines (IL-1β and IL-6) in AD brains. These findings are consistent with previous reports suggesting that RIPK1 is involved in different inflammatory diseases. ,, …”

Section: Discussionmentioning

confidence: 99%

“…These findings are consistent with previous reports suggesting that RIPK1 is involved in different inflammatory diseases. 28,29,32 Journal of Medicinal Chemistry In this study, only one dose was used to clarify the ameliorate effect of SZM679 in the cognitive dysfunction of mice. Furthermore, in vivo dose-dependent response would be carried out to understand the effect of the compound comprehensively, and more experiments should be performed for demonstrating the pharmacokinetics of SZM679 in mice including the concentration of SZM679 in brain.…”

Section: Szm679 Treatment Decreases the Expression Levels Of Inflamma...mentioning

confidence: 99%

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Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer’s Disease

Sun

Shao

et al. 2022

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Receptor-interacting protein kinase 1 (RIPK1) contributes to a broad set of inflammations and necroptosis in human diseases, which also plays an important role in the pathogenesis of Alzheimer’s disease (AD). The inhibition of RIPK1 could be a novel strategy to improve cognitive function. SZM679, a highly specific RIPK1 inhibitor (K d,RIPK1 = 8.6 nM, K d,RIPK3 > 5000 nM), was developed by our group with superior high antinecroptotic activity (EC50 = 2 nM), and investigated to completely reverse the tumor necrosis factor-induced systemic inflammatory response syndrome. In a streptozocin-induced AD-like mouse model, behavioral tests showed that SZM679 apparently ameliorated learning and memory dysfunction. Nissl staining revealed that SZM679 improved neuronal loss. Moreover, the Tau hyperphosphorylation, neuroinflammation, and the RIPK1 phosphorylation level in the hippocampus and cortex were significantly decreased in the SZM679-treated group. Collectively, SZM679 represents a promising lead structure for the discovery of novel RIPK1 inhibitory anti-AD agents.

“…PROTACs bring the POI and the E3 ligase into proximity to form a ternary complex and then induce the ubiquitination of the POI for depletion by the 26S proteasome . The degradation process induced by PROTACs is an event-driven pharmacological mechanism independent of sustained interactions with the target, which is different from the occupancy-driven mode of traditional inhibitors. − Thus, this event-driven approach has several advantages for noncatalytic protein targets, overexpressed targets, and mutant targets …”

Section: Introductionmentioning

confidence: 99%

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Cai

et al. 2022

Targeted protein degradation (TPD), a promising therapeutic strategy in drug discovery, has great potential to regulate the endogenous degradation of undruggable targets with small molecules. As vital resources that provide diverse structural templates for drug discovery, natural products (NPs) are a rising and robust arsenal for the development of therapeutic TPD. The first proof-of-concept study of proteolysis-targeting chimeras (PROTACs) was a natural polyketide ovalicin-derived degrader; since then, NPs have shown great potential to promote TPD technology. The use of NP-inspired targeted protein degraders has been confirmed to be a promising strategy to treat many human conditions, including cancer, inflammation, and nonalcoholic fatty liver disease. Nevertheless, the development of NP-inspired degraders is challenging, and the field is currently in its infancy. In this review, we summarize the bioactivities and mechanisms of NP-inspired degraders and discuss the associated challenges and future opportunities in this field.