更新于：2023-09-14

NLRP3 inflammasome inhibitor(Exscientia/University of Oxford)

更新于：2023-09-14

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名-

靶点

NLRP3(含 NACHT, LRR 和PYD 结构域蛋白-3)

作用机制

NLRP3抑制剂(含 NACHT, LRR 和PYD 结构域蛋白-3抑制剂)

治疗领域

神经系统疾病

在研适应症

阿尔茨海默病

非在研适应症-

原研机构

Exscientia AI Ltd.

在研机构

University of Oxford

Exscientia AI Ltd.

非在研机构-

最高研发状态(全球)药物发现

首次获批日期(全球)-

最高研发状态(中国)-

特殊审评-

关联

100 项与 NLRP3 inflammasome inhibitor(Exscientia/University of Oxford) 相关的专利（医药）

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210

项与 NLRP3 inflammasome inhibitor(Exscientia/University of Oxford) 相关的文献（医药）

2023-08-14·Clinical pharmacology in drug development

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZY-IL1 in Three Patients with Cryopyrin-Associated Periodic Syndromes.

Article

作者: Pravin Hissaria ; Kevinkumar Kansagra ; Hardik Patel ; Taufik Momin ; Ashok Ghoghari ; Harilal Patel ; Bhavesh Sharma

We present the first results of the proof-of-concept phase 2a study of oral NLRP3 inflammasome inhibitor in subjects with cryopyrin-associated periodic syndromes (CAPS). Three adult subjects with a confirmed diagnosis of CAPS were enrolled and administered 50 mg of ZYIL1 twice daily for 7 days. A total of 5 treatment-emergent adverse events (TEAEs) were reported in 2 subjects. All 5 TEAEs were mild in severity and considered unrelated to the study drug. At steady state, the average plasma concentration and trough concentration ranged from 2.5 to 4.2 and 1.4 to 2.5 μg/mL, respectively. Inflammatory markers and disease activity (physician and patient global assessment score) decreased notably 12 hours post-last dose.

2023-07-20·Journal of cellular physiology

Hyperuricemia promotes the progression of atherosclerosis by activating endothelial cell pyroptosis via the ROS/NLRP3 pathway.

Article

作者: Bin He ; Qiangqiang Nie ; Feng Wang ; Xuming Wang ; Yun Zhou ; Cheng Wang ; Jing Guo ; Xueqiang Fan ; Zhidong Ye ; Peng Liu ; Jianyan Wen

Hyperuricemia closely correlates with the development of atherosclerosis, but little is known of the mechanism by which atherosclerosis progression occurs in hyperuricemia. Atherosclerosis appears to involve pyroptosis, an emerging mechanism of proinflammatory regulated cell death. This study tested the hypothesis that pyroptosis underlies the relationship between hyperuricemia and atherosclerosis, using ApoE^-/- mice (a model of atherosclerosis), human umbilical vein endothelial cells (HUVECs), and human atherosclerotic arterial samples. We found that hyperuricemia can aggravate the aortic atherosclerotic plaque-load in ApoE^-/- mice and promote endothelial cell pyroptosis. Additionally, hyperuricemia can increase the levels of serum inflammatory factors (including IL-1β and IL-18). Exposure to lipopolysaccharide plus a high concentration of soluble uric acid (≥12 mg/dL) induced cell pyroptosis in HUVECs, as evidenced by increased expression of pyroptosis-related proteins and elevated release of lactate dehydrogenase (a marker of tissue damage). Further, MCC950, a selective nucleotide-binding oligomerization domain (NOD)-like receptor 3 (NLRP3) inflammasome inhibitor, and N-acetyl- l-cysteine, an antioxidant, attenuated HUVEC pyroptosis by inhibiting activation of the NLRP3 inflammasome and production of intracellular reactive oxygen species (ROS). Finally, we detected significantly higher expression of pyroptosis-associated proteins in carotid specimens from patients with hyperuricemia. Collectively, our findings suggest that hyperuricemia can aggravate endothelial cell pyroptosis in aortic atherosclerotic plaques, promoting the development of atherosclerosis. Additionally, a high concentration of soluble uric acid can trigger the activation stage of the NLRP3 inflammasome, mediating endothelial cell pyroptosis, and this process is regulated by the cellular ROS level.

2023-07-01·Immunity, inflammation and disease

Evidence on the therapeutic role of thiolutin in imiquimod-induced psoriasis-like skin inflammation in mice.

Article

作者: Aixue Wang ; Xixing Ma ; Feng Wei ; Yanling Li ; Qiang Liu ; Huanhuan Zhang

INTRODUCTION:

A recent study confirmed that thiolutin (THL), as a potent inflammasome inhibitor, plays a promising therapeutic role in multiple inflammatory disease models. However, the effect of THL on psoriasis has not been reported so far.

METHODS:

A psoriasiform dermatitis model was prepared by applying 5% imiquimod (IMQ) cream on mice. A total of 36 mice were randomly divided into six groups: control, model, model + THL-L/M/H (THL, 1/2.5/5 mg/kg/day), model + methotrexate (1 mg/kg/day). Psoriasis area and severity index (PASI) scores were observed and calculated. The histological changes in skin, liver, and kidney tissues were observed by hematoxylin and eosin staining. Alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and blood creatinine were measured by automatic biochemistry analyzer. The size of the spleens was determined, and the proportion of Foxp3 + CD4+ regulatory T (Treg) cells in the spleens was tested by flow cytometry. The proinflammatory factors and nucleotide oligomerization domain nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome protein levels were examined by reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunohistochemistry, respectively.

RESULTS:

THL administration preeminently reduced the thickness, scaling, and erythema of the skin lesions, alleviated IMQ-induced psoriasiform lesions in mice, reduced the PASI score, and ameliorated histopathological changes in mouse skin. The spleen index was decreased by almost half and the proportion of Foxp3 + CD4+ Treg cells was increased after intervention by THL. THL intervention did not affect liver and kidney function, but decreased the expression levels of proinflammatory factors and NLRP3 inflammasome in the skin of psoriatic mice.

CONCLUSIONS:

THL may alleviate IMQ-induced psoriasis-like manifestations in mice by inhibiting NLRP3 inflammasome.

项与 NLRP3 inflammasome inhibitor(Exscientia/University of Oxford) 相关的新闻（医药）

2023-09-07

·PRNewswire

Adiso Therapeutics to Participate in Upcoming September Investor Conferences

CONCORD, Mass., Sept. 7, 2023 /PRNewswire/ -- Adiso Therapeutics, Inc., a clinical-stage biotechnology company committed to creating medicines that treat inflammatory diseases and improve the lives of patients and their families, today announced that Scott Megaffin, Chief Executive Officer, and members of the Adiso Corporate Staff will participate in the following upcoming investor conferences: Baird 2023 Global Healthcare Conference Presentation Date/Time: Wednesday, September 13, 2023, at 3:45 p.m. ET Location: IHG Hotel, New York City, NY Webcast: A replay of the presentation will be available on the Adiso website under the "News & Events" page H.C. Wainwright 25th Annual Global Investment Conference Date: September 11-13, 2023 Location: Lotte New York Palace Hotel, New York City, NY Cantor Global Healthcare Conference Date: September 26-28, 2023 Location: InterContinental Barclay Hotel, New York City, NY Members of the Adiso management team will be available for one-on-one meetings during these conferences. About Adiso:  Adiso is a clinical-stage biopharmaceutical company dedicated to improving the health of patients suffering from debilitating inflammatory diseases. This dedication is epitomized by our lead clinical candidates, which exemplify 'healthruption' (disruption in healthcare and drug development) with novel mechanisms of action and a distinct approach to the treatment of inflammatory diseases. ADS051, an oral gut-restricted modulator of neutrophil trafficking and activation via inhibition of MRP2 and FPR1 for the treatment of ulcerative colitis; and ADS032, a dual NLRP1/NLRP3 inflammasome inhibitor initially being developed for inflammatory diseases of the lung. Adiso has built these development programs upon a rich history of institutional and academic collaboration, including the, the University of Massachusetts Chan Medical School, the Hudson Institute of Medical Sciences Centre for Innate Immunity and Infectious Diseases in Australia, the University of Edinburgh Centre for Inflammation Research and the University College Cork, Ireland, the APC Microbiome Institute. For more information, please visit or our LinkedIn page.  Contacts Argot Partners Media: Sarah Sutton/Liza Sullivan IR: Jason Finkelstein [email protected] 212.600.1902 Adiso Therapeutics, Inc. Scott Megaffin, Chief Executive Officer [email protected] Jennifer Locke, Chief Operating & Business Officer [email protected] 978.202.4335 SOURCE Adiso Therapeutics

2023-09-07

·BioSpace

Adiso Therapeutics to Participate in Upcoming September 2023 Investor Conferences

CONCORD, Mass., Sept. 7, 2023 /PRNewswire/ -- Adiso Therapeutics, Inc., a clinical-stage biotechnology company committed to creating medicines that treat inflammatory diseases and improve the lives of patients and their families, today announced that Scott Megaffin, Chief Executive Officer, and members of the Adiso Corporate Staff will participate in the following upcoming investor conferences: Baird 2023 Global Healthcare Conference Presentation Date/Time: Wednesday, September 13, 2023, at 3:45 p.m. ET Location: IHG Hotel, New York City, NY Webcast: A replay of the presentation will be available on the Adiso website under the "News & Events" page H.C. Wainwright 25th Annual Global Investment Conference Date: September 11-13, 2023 Location: Lotte New York Palace Hotel, New York City, NY Cantor Global Healthcare Conference Date: September 26-28, 2023 Location: InterContinental Barclay Hotel, New York City, NY Members of the Adiso management team will be available for one-on-one meetings during these conferences. About Adiso: Adiso is a clinical-stage biopharmaceutical company dedicated to improving the health of patients suffering from debilitating inflammatory diseases. This dedication is epitomized by our lead clinical candidates, which exemplify 'healthruption' (disruption in healthcare and drug development) with novel mechanisms of action and a distinct approach to the treatment of inflammatory diseases. ADS051, an oral gut-restricted modulator of neutrophil trafficking and activation via inhibition of MRP2 and FPR1 for the treatment of ulcerative colitis; and ADS032, a dual NLRP1/NLRP3 inflammasome inhibitor initially being developed for inflammatory diseases of the lung. Adiso has built these development programs upon a rich history of institutional and academic collaboration, including the, the University of Massachusetts Chan Medical School, the Hudson Institute of Medical Sciences Centre for Innate Immunity and Infectious Diseases in Australia, the University of Edinburgh Centre for Inflammation Research and the University College Cork, Ireland, the APC Microbiome Institute. For more information, please visit or our LinkedIn page. Contacts Argot Partners Media: Sarah Sutton/Liza Sullivan IR: Jason Finkelstein Adiso@argotpartners.com 212.600.1902 Adiso Therapeutics, Inc. Scott Megaffin, Chief Executive Officer smegaffin@adisotx.com Jennifer Locke, Chief Operating & Business Officer pr@adisotx.com 978.202.4335 View original content to download multimedia: SOURCE Adiso Therapeutics

2023-08-31

·PRNewswire

Halia Therapeutics to Present at the 17th Annual PAINWeek Conference

SALT LAKE CITY, Aug. 31, 2023 /PRNewswire/ -- Halia Therapeutics, a clinical-stage biopharmaceutical company advancing innovative medicines to treat a broad range of diseases driven by chronic inflammation and neurodegeneration, today announced they will be presenting new data at the 17th Annual PAINWeek Conference on Thursday, September 7, at 5:30 p.m. PDT/8:30 p.m. EDT. Halia's presentation will highlight the recent company developments on its NLRP3 inflammasome inhibitor and lead asset, HT-6184, and how it was able to mitigate both thermal hyperalgesia and mechanical allodynia in a dose-dependent manner in the Complete Freund's Adjuvant-Induced pain rat model. "Inflammation plays a crucial role in pain perception, and these research findings showcase the important downstream effects of Halia's innovative therapy to target the inflammasome and treat pain," said Dr. David J. Bearss, President and CEO of Halia Therapeutics. "The results support HT-6184's potential to significantly reduce post-procedural pain and disease-induced pain associated with inflammatory signals and chronic inflammation in humans. With the recently completed enrollment in our Phase I clinical trial of HT-6184, we look forward to analyzing the results and advancing our clinical development." Details about the poster presentation are as follows: Title: Characterization of the NLRP3 Inflammasome Inhibitor HT-6184 in the Complete Freund's Adjuvant (CFA)-Induced Pain Model Presenter: Devan Bursey, M.S., Scientist at Halia Therapeutics Date: Thursday, September 7, 2023, from 5:30 p.m. – 6:30 p.m. PDT Location: The Cosmopolitan, Las Vegas, NV About NLRP3 Activation of NLRP3 triggers the release of the pro-inflammatory cytokines IL-1β and IL-18 and induces a lytic cell death process called pyroptosis. These processes lead to systemic chronic inflammation. Halia's therapeutic inhibition of NLRP3 prevents the formation of the NLRP3 inflammasome and promotes its disassembly once formed, thereby inhibiting the production and release of IL-1β and IL-18. Persistent activation of the NLRP3 inflammasome is thought to drive the onset and progression of many conditions, including fibrotic, dermatological, and auto-inflammatory diseases. Significant neurological disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis are also driven by NLRP3 activation. About HT-6184 HT-6184 is the first drug candidate to target the protein NEK7 through an allosteric mechanism. NEK7 is an essential component of the NLRP3 inflammasome and is critical for its assembly and the maintenance of NLRP3 activity. In preclinical models, Halia has shown that inhibiting the ability of NEK7 to bind to NLRP3 leads to a disruption in the formation of the NLRP3 inflammasome complex, thereby inhibiting the signaling from the inflammasome and reducing the inflammatory response. Preclinical models also showed that in addition to disrupting the formation of the NLRP3 inflammasome, HT-6184 promotes the disassembly of the inflammasome once activated. About Halia Therapeutics, Inc. Halia Therapeutics is discovering and developing a pipeline of novel therapeutics to improve patients' lives with chronic inflammatory disorders and neurodegenerative diseases, with its initial programs targeting NEK7 and LRRK2. Halia's lead candidate, HT-6184, a novel NEK7/NLRP3 inhibitor, has completed a Phase 1 study (NCT05447546) evaluating the safety and tolerability of HT-6184 when administered as single or multiple oral doses at escalating dose levels in healthy volunteer subjects. The company is headquartered in Salt Lake City, Utah. For more info, visit or follow us on LinkedIn and Twitter (X). Company Contact: James Dye [email protected] +1.385.355.4315 Media Contact: Ignacio Guerrero-Ros, Ph.D. Russo Partners, LLC +1 (646) 942-5604 [email protected] SOURCE Halia Therapeutics

临床1期