Aberrant activation of the NLRP3 inflammasome drives the pathogenesis of numerous human inflammatory diseases, highlighting the urgent need for small-molecule inhibitors targeting NLRP3. Building upon the lead compound 15z, we designed and synthesized a novel series of benzoxazole derivatives and conducted preliminary structure-activity relationship (SAR) studies. The representative compound D12 exhibited more potent NLRP3 inflammasome inhibitory activity than compound 15z, with an IC₅₀ value of 94.15 nM. Mechanistic studies revealed that D12 directly targets the NACHT domain of NLRP3 protein (K_D = 558.4 nM), effectively blocking inflammasome assembly and activation, thereby exerting anti-inflammatory effects. In vivo study showed that D12 significantly increased the survival time in a murine model of LPS-induced sepsis. Our findings indicate that compound D12 is a promising NLRP3 inhibitor, providing a new approach for the discovery of anti-inflammatory drugs.

2026-07-01·MICROBIAL PATHOGENESIS

Autophagy induced by Trichinella spiralis infection alleviate TNBS-induced colitis in mice through inhibiting the NLRP3 inflammasome

Article

作者: Kang, Xinyi ; Zhang, Yanan ; Wang, Jianzhong ; Liu, Xuanrui ; Zhang, Zhiyuan ; Wang, Yuxin ; Wang, Chunfeng ; Huang, Haibin ; Yang, Wentao ; Zeng, Yan ; Cao, Xin ; Zhang, Jingwei ; Yang, Guilian ; Jiang, Yanlong ; Wang, Nan ; Shi, Chunwei

BACKGROUND:

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a group of chronic intestinal inflammatory disorders with diverse etiologies and limitations in current treatments. Trichinella spiralis, a foodborne parasitic nematode, has been reported to alleviate colitis in mouse models, but its specific mechanism remains unclear.

METHODS:

This study aims to investigate whether T. spiralis-induced autophagy can alleviate IBD by inhibiting the NLRP3 inflammasome. Experimental colitis was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice 21 days after T. spiralis infection. Experimental groups were treated with 3-methyladenine (3-MA, autophagy inhibitor), rapamycin (Rapa, autophagy activator), or MCC950 (NLRP3 inhibitor), respectively. The severity of enteritis, the levels of autophagy and NLRP3 inflammasome activity, were evaluated using colon length, body weight, disease activity index (DAI) scores, hematoxylin-eosin (H&E) staining, myeloperoxidase (MPO) activity assay, flow cytometry, qPCR, and Western blot.

RESULTS:

The results revealed that T. spiralis infection alleviated colitis, concurrent with enhanced autophagy and suppressed NLRP3 inflammasome activation. Notably, inhibition of autophagy led to aggravated colitis symptoms and concomitant activation of the NLRP3 inflammasome. In contrast, autophagy activation resulted in attenuated colitis manifestations and inhibition of the NLRP3 inflammasome. Moreover, direct inhibition of the NLRP3 inflammasome was capable of alleviating colitis.

CONCLUSIONS:

This study reveals that T. spiralis can alleviate IBD by inducing autophagy to inhibit the NLRP3 inflammasome, providing new insights into the treatment of IBD.

2026-05-22·JOURNAL OF NATURAL PRODUCTS

An Integrated Approach Combining Chemical Profiling, Network Pharmacology, and In Vitro Validation to Uncover the Multitarget Mechanisms of Naokang II Decoction against Vascular Dementia

Article

作者: Chen, Yujing ; Ren, Weiquan ; Wang, Feixue ; Rausch, Wolf-Dieter ; Shen, Ying ; Fan, Xinyue ; Wu, Xiling

Vascular dementia (VaD) is a debilitating cognitive disorder with limited pharmacological treatments. Naokang II decoction (NKII) is a traditional Chinese medicine (TCM) formula for VaD with significant efficacy, but its mechanisms remain unclear. This study integrated chemical profiling, network pharmacology, single-nucleus RNA sequencing (snRNA-seq) analysis, molecular docking, and in vitro validation to elucidate NKII's mechanisms against VaD. LC-MS/MS identified 412 components in NKII, of which 45 compounds were screened as active constituents. Their 1081 predicted targets overlapped with 1592 VaD-related dysregulated genes, yielding 73 common targets. Network analysis identified 10 core targets, including NLRP3, CASP1, and TLR2. snRNA-seq data localized these core targets predominantly to microglia. Molecular docking revealed that the coumarin Herniarin, a component newly identified in NKII, exhibited the strongest binding affinity to NLRP3. In vitro experiments on BV2 and HMC3 microglial cells showed that Herniarin inhibited cell proliferation and migration, induced apoptosis, arrested the cell cycle at the G2/M phase, and downregulated TLR2, NLRP3, ASC, and CASP1 at both mRNA and protein levels, exerting antineuroinflammatory effects by inhibiting the microglial NLRP3 inflammasome pathway. This study established a multidimensional research paradigm and identified Herniarin as a novel NLRP3 inhibitor with therapeutic potential for VaD and other neuroinflammatory diseases.

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

登录后查看更多信息