As a key intracellular pattern-recognition receptor, NLRP3 senses diverse pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammasome assembly and pyroptotic cell death. Aberrant NLRP3 activation contributes to various chronic inflammatory diseases, including atherosclerosis, Alzheimer's disease, and rheumatoid arthritis, underscoring its therapeutic relevance. In this study, we designed and synthesized compound 8a, a structurally optimized derivative of the diterpenoid alkaloid songorine. In lipopolysaccharide (LPS)- and nigericin-stimulated macrophage models, 8a markedly reduced lactate dehydrogenase (LDH) release (IC₅₀ = 2.69 μM in THP-1 cells and 1.75 μM in J774A.1 cells) and effectively inhibited gasdermin D (GSDMD) cleavage and interleukin-1β (IL-1β) secretion, demonstrating potent suppression of pyroptosis. Hydrogenation of the C16-C17 double bond afforded compound 8b, which lost inhibitory activity, indicating that the α,β-unsaturated carbonyl moiety is essential for function, likely via covalent modification of cysteine residues on NLRP3. This mechanism was further substantiated by Drug Affinity Responsive Target Stability (DARTS) assays and mass spectrometry, confirming direct binding between 8a and NLRP3. We also conducted structure-activity relationship studies by modifying the C1 position and found that such modifications did not significantly impact the compound's activity. Collectively, these findings identify 8a as a novel songorine-derived covalent NLRP3 inhibitor and provide the first elucidation of its structure-activity relationship and molecular mechanism, offering valuable insights for the rational design of safe and effective anti-inflammatory agents targeting NLRP3.

2026-03-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Rational design of an NLRP3 inhibitor with superior efficacy and safety for gout therapy

Article

作者: Ren, Shuhua ; Guo, Yue ; Jiang, Caihong ; Kong, Yichao ; Huang, Weiwei ; Hu, Yingjie ; Qiu, Ting ; Zhu, Fuli ; Mao, Zhenyu ; Yuan, Yaxia ; Li, Donglai ; Feng, Haonan ; Chi, Man ; Su, Mengjun ; Liu, Fengling ; Ma, Lei ; Chen, Xiabin

Gout, driven by urate crystal-induced inflammation, remains a therapeutic challenge due to the limited efficacy and toxicity of current treatments. Targeting the NLRP3 inflammasome, a central driver of gout pathogenesis, offers a promising strategy. While MCC950, a potent NLRP3 inhibitor, demonstrated clinical potential, its discontinuation due to hepatotoxicity underscores the urgent need for safer alternatives. Here, we address these challenges through a rational drug design approach to develop next-generation NLRP3 inhibitors. By leveraging cryo-EM structures and molecular dynamics (MD) simulations of the MCC950-NLRP3 complex, we identified a structurally dynamic region near the furan moiety and an adjacent unoccupied hydrophobic pocket. Systematic structural optimization targeting this pocket enabled the design of M48, a derivative that exhibited superior anti-inflammatory activity (IC₅₀ = 11.9 nM), favorable oral bioavailability (89.7 % in rats), and an improved safety profile compared to MCC950. In an MSU-induced mouse gout model, M48 demonstrates superior anti-inflammatory and analgesic effects compared to indomethacin, with efficacy comparable to colchicine. The design strategy, grounded in computational insights into ligand-protein interactions, demonstrates both scientific rigor and broad applicability for optimizing small-molecule inhibitors. Notably, M48's enhanced efficacy and reduced liver toxicity risk validate the approach's potential for addressing unmet clinical needs in gout and other NLRP3-associated diseases.

2026-01-01·INTERNATIONAL IMMUNOPHARMACOLOGY

Nimbolide inhibits NLRP3 inflammasome activation via blocking NEK7-NLRP3 interaction and alleviates sepsis-induced lung injury

Article

作者: Li, JunMei ; Wang, XueYi ; Li, ZhanChuan ; Gong, HuanHuan ; Bai, Yang ; Yu, BoWen

BACKGROUND:

Sepsis-associated acute lung injury (ALI) remains a critical clinical challenge with limited therapeutic options. The NLRP3 inflammasome drives pathological inflammation in ALI, yet clinical translation of existing inhibitors is hindered by toxicity. Natural products offer safer alternatives, but their mechanisms in targeting NLRP3 assembly are poorly defined.

METHODS:

We screened a natural compound library for NLRP3 inhibitors using LPS/nigericin-stimulated murine peritoneal macrophages, measuring IL-1β release by ELISA. Mechanistic studies included immunoprecipitation (NEK7-NLRP3/ASC-NLRP3 interactions), ASC oligomerization/speck formation assays, DARTS, CETSA, and molecular docking. In vivo efficacy was evaluated in LPS-induced ALI and endotoxemia mouse models (histopathology, cytokine analysis, immunoblotting).

RESULTS:

Nimbolide was identified as a potent NLRP3 inhibitor. It dose-dependently suppressed IL-1β secretion and caspase-1/GSDMD cleavage in murine/human (THP-1) macrophages, without affecting AIM2/NLRC4 inflammasomes or TNF-α production. Mechanistically, Nimbolide disrupted NEK7-NLRP3 binding and ASC oligomerization, thereby blocking NLRP3 inflammasome assembly. Further investigations revealed that Nimbolide enhanced the thermal stability of NLRP3 as demonstrated by the cell thermal shift assay (CETSA), conferred protease resistance as evidenced by the drug affinity responsive target stability (DARTS) assay, and exhibited high-affinity binding to NLRP3 with a binding energy of -7.62 kcal/mol through molecular docking studies. These results collectively suggest that Nimbolide can directly bind to NLRP3. In vivo, Nimbolide reduced pulmonary IL-1β levels, suppressed GSDMD cleavage, and attenuated lung injury pathology.

CONCLUSION:

Nimbolide is a new natural inhibitor that selectively targets the NLRP3 interface and block NLRP3 inflammasome activation, offering a promising therapeutic strategy for NLRP3-driven inflammatory disorders like sepsis-associated ALI.

项与 NLRP3 inhibitor(WuXi AppTec) 相关的新闻（医药）

2026-01-21

·FierceBiotech

Insilico agrees on $66M deal to split rights for preclinical NLRP3 inhibitor with new Chinese biotech

Insilico Medicine noted ISM8969’s \"desirable blood–brain barrier penetration.\"\n Artificial-intelligence-powered drug developer Insilico Medicine is set for a $10 million upfront payment from a fresh-faced Chinese biotech for half of the rights to a brain-penetrant NLRP3 inhibitor.Under the agreement, Insilico will take the lead on bringing the preclinical asset, dubbed ISM8969, into a phase 1 trial for Parkinson’s disease. Hygtia Therapeutics will then take over for further studies and onward toward regulators and commercialization.As well as the upfront fee, Insilico is in line for up to $56 million in milestone payments from Hygtia.Interest in NLRP3 inhibition as a way to address a range of neuroinflammatory and cardiometabolic diseases has ramped up in the past year. Earlier this month, Eli Lilly paid $1.2 billion to acquire Ventyx Biosciences in the wake of a phase 2 study tying Ventyx’s lead NLRP3 inhibitor to improvements in Parkinson’s symptoms.That same NLRP3 inhibitor had also been shown to cut levels of a biomarker for stroke and other serious risks by almost 80% within a week in a separate midstage study.When it comes ISM8969, preclinical data have already “demonstrated the molecule\'s robust efficacy, favorable safety profile and marked anti-inflammatory activity in various disease models,” said Insilico, which also noted the therapy’s “desirable blood–brain barrier penetration.”Insilico, which went public on the Hong Kong Stock Exchange last month, said it had discovered ISM8969 via its generative chemistry engine Chemistry42.“Targeting neuroinflammation via NLRP3 represents a scientifically sound and high-potential approach to treating neurodegenerative and age-related diseases,” Insilico co-CEO and Chief Scientific Officer Ren Feng, Ph.D., said in the release. “However, developing a safe molecule with good blood-brain barrier penetration remains a formidable obstacle for drug developers,” Feng added.“Through our generative AI platform, we have designed a molecule specifically engineered to overcome this barrier,” he said. “We are pleased to partner with Hygtia Therapeutics. We believe that through our combined efforts, we can accelerate its clinical progress to address significant unmet medical needs.”Insilico has found it easy to attract Big Pharma interest for its AI-enabled drug discovery tech, including the likes of Sanofi, Pfizer, Menarini Group and Boehringer Ingelheim. Most recently, Lilly penned a $100 million-plus biobucks deal in November.Hygtia, which was founded last August after being incubated by Fosun Pharma, said the agreement with Insilico “marks a pivotal step in our global strategy.”“This partnership aligns with our strategy to expand our innovative neuroscience pipeline through high-quality assets,” the fresh-faced biotech added.

临床2期临床1期并购引进/卖出

2025-11-03

·BioSpace

Neurocrine Goes to China To Grow Pipeline in up to $881M TransThera Deal

iStock, jozefmicic At the center of the licensing deal is an NLRP3 inhibitor that has shown “encouraging efficacy in acute inflammation models,” according to TransThera, indicating its potential in various metabolic and inflammatory diseases. Neurocrine is joining the gold rush of companies finding assets in China, licensing an NLRP3 inhibitor in a deal with the Nanjing-based TransThera Sciences. Under the terms of the agreement, TransThera will receive an upfront payment along with R&D and sales milestones that could total $881.5 million, the company revealed in a press release Monday. The deal gives Neurocrine rights outside of greater China—including mainland China, Hong Kong, Taiwain and Macao—to TransThera’s portfolio of NLRP3 inhibitors. While the company’s pipeline only lists one candidate, called TT-02332, in that portfolio, TransThera’s release suggests more than one molecule available for licensing. Under the terms of the deal, Neurocrine and TransThera will develop NLRP3 inhibitors for “multiple diseases.” What specific indications could be targeted using the molecule or molecules were not revealed. However, TransThera said, “TT-02332 has shown encouraging efficacy in acute inflammation models, indicating its potential application in various metabolic and inflammatory diseases.” NLRP3 proteins are involved in the inflammasome, an innate cellular response to infection that promotes inflammation. Overactive activation of proteins in the inflammasome pathway are implicated in a number of diseases, including diabetes, atherosclerosis and Alzheimer’s disease. Neurocrine is on the upswing, recently announcing total sales of $790 million for the third quarter of 2025, a 28% year-over-year growth. However, the company is relying almost exclusively on one asset and might be looking to broaden its pipeline. In Q3, $687 million of its Neurocrine’s income came from sales of Ingrezza, its treatment for the movement disorder tardive dyskinesia, as well as chorea associated with Huntington’s disease. Rounding out Neurocrine’s sales was Crenessity, its treatment for congenital adrenal hyperplasia, which reeled in $98 million. Neurocrine made another move to diversify its assets earlier this year, grabbing the depression treatment osavampator from its long-term partner Takeda. That molecule scored a major win in a Phase II trial in 2024, significantly easing symptoms of major depressive disorder in comparison to placebo.

引进/卖出临床2期

100 项与 NLRP3 inhibitor(WuXi AppTec) 相关的药物交易

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