作者: Li, Xun ; Yuan, Xiaomin ; Zhang, Wei ; Shu, Yi ; Chen, Zepeng ; Chen, Kaidi ; Wang, Yuji ; Chen, Yugen ; Chen, Chen ; Wang, Peimin ; Chen, Tuo ; Tang, Wenwen ; Shi, Guoping ; Ma, Jiaze ; Wang, Kuiling

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with immune dysregulation affecting colon inflammatory response. Recent studies have highlighted that neutrophil extracellular traps (NETs) play an important role in the pathogenesis of UC. Berbamine (BBM), one of the bioactive ingredients extracted from Chinese herbal medicine Berberis vulgaris L, has attracted intensive attentions due to its significant anti-inflammatory activity and a marketing drug for treating leukemia in China. However, the exact role and potential molecular mechanism of BBM against UC remains elusive. In the present study, our results showed that BBM could markedly improve the pathological phenotype and the colon inflammation in mice with dextran sulfate sodium (DSS)-induced colitis. Then, comprehensive approaches combining network pharmacology and molecular docking analyses were employed to predict the therapeutic potential of BBM in treating UC by peptidyl-arginine deiminase 4 (PAD4), a crucial molecule involved in NETs formation. The molecular docking results showed BBM had a high affinity for PAD4 with a binding energy of -9.3 kcal/mol Moreover, PAD4 expression and NETs productions, including citrullination of histone H3 (Cit-H3), neutrophil elastase (NE), myeloperoxidase (MPO) in both neutrophils and colonic tissue were reduced after BBM administration. However, in the mice with DSS-induced colitis pretreated with GSK484, a PAD4-specific inhibitor, BBM could not further reduce disease related indexes, expression of PAD4 and NETs productions. Above all, the identification of PAD4 as a potential target for BBM to inhibit NETs formation in colitis provides novel insights into the development of BBM-derived drugs for the clinical management of UC.

2024-06-01·Journal of Thrombosis and Haemostasis

Involvement of peptidylarginine deiminase 4 in eosinophil extracellular trap formation and contribution to citrullinated histone signal in thrombi

Article

作者: Denorme, Frederik ; Crescente, Marilena ; Van Bruggen, Stijn ; Witsch, Thilo ; Glatz, Katharina ; Grandhi, Ramesh ; Siegel, Patrick M ; Stroobants, Mathias ; Meyers, Severien ; Martinod, Kimberly

BACKGROUNDExtracellular traps formed by neutrophils (NETs) and eosinophils (EETs) have been described in coronary thrombi, contributing to thrombus stability. A key mechanism during NET formation is histone modification by the enzyme PAD4. Citrullinated histones, the product of PAD4 activity, are often attributed to neutrophils. Eosinophils also express high levels of PAD4.OBJECTIVESWe aimed to explore the contribution of PAD4 to EET formation.METHODSWe performed immunohistological analyses on thrombi, including a large, intact, and eosinophil-containing thrombus retrieved from the right coronary artery using an aspiration catheter and stroke thrombi from thrombectomy retrieval. We studied eosinophils for their capability to form PAD4-dependent EETs in response to strong ET-inducing agonists as well as activated platelets and bacteria.RESULTSHistopathology and immunofluorescence microscopy identified a coronary thrombus rich in platelets and neutrophils, with distinct areas containing von Willebrand factor and citrullinated histone H3 (H3Cit). Eosinophils were also identified in leukocyte-rich areas. The majority of the H3Cit+ signal colocalized with myeloperoxidase, but some colocalized with eosinophil peroxidase, indicating EETs. Eosinophils isolated from healthy volunteers produced H3Cit+ EETs, indicating an involvement of PAD4 activity. The selective PAD4 inhibitor GSK484 blocked this process, supporting PAD4 dependence of H3Cit+ EET release. Citrullinated histones were also present in EETs produced in response to live Staphylococci. However, limited evidence for EETs was found in mouse models of venous thrombosis or infective endocarditis.CONCLUSIONAs in NETosis, PAD4 can catalyze the formation of EETs. Inhibition of PAD4 decreases EET formation, supporting the future utility of PAD4 inhibitors as possible antithrombotic agents.

2024-05-23·Journal of Medicinal Chemistry

A β-Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment against Triple-Negative Breast Cancer

Article

作者: Deng, Qian ; Zhu, Di ; Hu, Bo ; Wang, Wenjing ; Lu, Yu ; Yan, Zhanchao ; Wang, Yuji ; Wang, Yanming ; Wang, Yinsong

Triple-negative breast cancer is a highly aggressive and heterogeneous breast cancer subtype characterized by early metastasis, poor prognosis, and high recurrence. Targeting histone citrullination-mediated chromatin dysregulation to induce epigenetic alterations shows great promise in TNBC therapy. We report the synthesis, optimization, and evaluation of a novel series of β-carboline-derived peptidyl arginine deiminase 4 inhibitors that exhibited potent inhibition of TNBC cell proliferation. The most outstanding PAD4 inhibitor, compound 28, hindered the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model. Furthermore, 28 improved the tumor immune microenvironment by reshaping neutrophil phenotype, upregulating the proportions of dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived suppressor cells. In conclusion, our work offered 28 as an efficacious PAD4 inhibitor that exerts a combination of conventional chemotherapy and immune-boosting effects, which represents a potential therapy strategy for TNBC.

项与 JBI-1044 相关的新闻（医药）

2023-08-24

·PRNewswire

Pharmaceutical Manufacturing Industry Forecast, 2030 | A ~$930 Billion Opportunity | Personalized Medicine Sparks Supply Chain Transformation to Accommodate Individualized Patient Care

DUBLIN, Aug. 24, 2023 /PRNewswire/ -- The "Pharmaceutical Manufacturing Industry Forecast, 2023-2030" report has been added to ResearchAndMarkets.com's offering. The global pharmaceutical manufacturing market is on a trajectory of significant growth, with an expected size of USD 929.9 billion by 2030. This growth is driven by several factors, including technological advancements, cost-effective methods, and increased investments in the pharmaceutical industry. The market is projected to grow at a Compound Annual Growth Rate (CAGR) of 7.63% from 2023 to 2030. Key Factors Driving Growth: Technological Advancements: The integration of robotic technology and Artificial Intelligence (AI) has enhanced efficiency and productivity in pharmaceutical manufacturing processes. These technologies have reduced downtime on the manufacturing floor and minimized product waste. Single-Use Disposable Solutions: The adoption of single-use disposable solutions has streamlined operations and lowered the risk of contamination. This shift has replaced traditional open-transfer manufacturing methods. Data-Rich Paperless Operations: The industry has embraced integrated, smart, and data-rich paperless operations, leading to precise and error-free production processes. This trend ensures the production of high-quality pharmaceutical products. Personalized Medicine: The development of personalized medicine has revolutionized healthcare by offering tailored treatments for individual patients. This shift has prompted manufacturers to adjust their supply chains to cater to smaller batches and patient-centric healthcare models. Strategic Initiatives by Key Players: Leading pharmaceutical companies are actively engaging in product development, collaboration, partnerships, business expansion, and mergers and acquisitions to strengthen their market presence and meet growing demand. Market Highlights: Conventional Drugs (Small Molecules): In 2022, the conventional drugs segment accounted for a significant revenue share, driven by the easy availability and high market penetration of small molecule products. Outsourcing: The outsourcing segment dominated the market in 2022 due to the various benefits associated with outsourcing operations, driving growth in this segment. Tablets: The tablets segment led the market with a considerable revenue share in 2022, attributed to the wide availability of tablet-based products with different formulations. Oral Dosage Forms: The oral segment dominated the global market due to affordability, ease of manufacturing, and patient-friendly nature of oral dosage forms. Prescription Medicines: Prescription medicines accounted for a substantial revenue share in 2022 and are expected to continue growing due to increasing prescription drug expenditures globally. North America: North America led the market in 2022, driven by strategic pharmaceutical partnerships and collaborations, especially among established and early-stage companies in the region. In summary, the global pharmaceutical manufacturing market is experiencing significant growth due to technological advancements, personalized medicine, and strategic initiatives by key players. Technological integration, the adoption of disposable solutions, and data-rich operations are enhancing efficiency and quality in pharmaceutical manufacturing. Additionally, the shift towards patient-centric healthcare models is prompting manufacturers to adjust their supply chains. With North America as a frontrunner, the pharmaceutical manufacturing market is poised for continued expansion over the forecast period. Key Attributes Market Dynamics Drivers Rise in Pharmaceutical R&D Spending Rise in Focus Toward Healthcare Needs in Emerging Nations Technological Advancements Increase in Geriatric Population and Incidence of Chronic Disorders Restraints Patent Expiration of Most Profitable Drugs Pricing Pressures on Bio/Pharmaceutical Companies Companies Mentioned F. Hoffmann-La Roche Ltd. Novartis AG GlaxoSmithKline plc Pfizer, Inc. Merck & Co. Inc. AstraZeneca Johnson & Johnson Services, Inc. Sanofi SA Eli Lilly and Company AbbVie, Inc. Thermo Fisher Scientific, Inc. Wuxi Apptec Samsung Biologics FUJIFILM Diosynth Biotechnologies U.S.A., Inc. Lonza Catalent Pharma Solutions Jubilant Pharmova Limited Key Topics Covered Chapter 1. Methodology and Scope Chapter 2. Executive Summary Chapter 3. Pharmaceutical Manufacturing Market Variables, Trends & Scope Chapter 4. Pharmaceutical Manufacturing: Molecule Type Estimates & Trend Analysis Chapter 5. Pharmaceutical Manufacturing: Drug Development Type Estimates & Trend Analysis Chapter 6. Pharmaceutical Manufacturing: Formulation Estimates & Trend Analysis Chapter 7. Pharmaceutical Manufacturing: Route of Administration Estimates & Trend Analysis Chapter 8. Pharmaceutical Manufacturing: Therapy Area Estimates & Trend Analysis Chapter 9. Pharmaceutical Manufacturing: Prescription Estimates & Trend Analysis Chapter 10. Pharmaceutical Manufacturing: Age Group Estimates & Trend Analysis Chapter 11. Pharmaceutical Manufacturing: Sales Channel Estimates & Trend Analysis Chapter 12. Pharmaceutical Manufacturing Market: Regional Estimates & Trend Analysis Chapter 13. Competitive Landscape For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

并购

2023-06-15

·PRNewswire

Jubilant Therapeutics Inc. Appoints Nadir Patel as an Independent Member of Its Board of Directors

BEDMINSTER, N.J., June 15, 2023 /PRNewswire/ -- Jubilant Therapeutics Inc., a clinical stage biopharmaceutical company advancing small molecule precision therapeutics to address unmet medical needs in oncology and autoimmune diseases, today announced the appointment of Nadir Patel as an independent director on the Company's Board of Directors. "Nadir Patel has had a distinguished career advising corporate executives in private industry and representing Canada in foreign affairs," said Hari S Bhartia, Chairman, Jubilant Therapeutics Inc . "His broad experience in strategic planning, finance, human resources and other disciplines will be invaluable as Jubilant Therapeutics Inc. continues to develop as a company and advances its differentiated drug pipeline in preclinical and clinical development." Nadir Patel is a senior strategic advisor at global law firm Norton Rose Fulbright Canada LLP, managing director at Fairfax Consulting Services and strategic advisor to the President of Huron University at Western. Prior to his current roles, Nadir held several senior government positions over a notable career in Canada's public service. Most recently, he served as Canada's High Commissioner for the Republic of India, with concurrent accreditation as Canada's Ambassador to Nepal and Ambassador to the Kingdom of Bhutan until 2021. He also previously served as Assistant Deputy Minister and Chief Financial Officer for Canada's Department of Foreign Affairs, Trade and Development and as Canada's Consul General in Shanghai. He currently serves on the board of directors of Canadian Tire Corporation where he also chairs the audit committee, as well as board Chairman at Canadian Tire Jumpstart Charities. Nadir Patel holds a joint MBA from New York University's Stern School of Business, London School of Economics and Political Science, and HEC (Paris) School of Management. About Jubilant Therapeutics Inc. Jubilant Therapeutics Inc. is a clinical stage biopharmaceutical company developing precision oral medicines with enhanced therapeutic index to address unmet medical needs in oncology and autoimmune diseases for genetically defined patients. Its advanced structure-based discovery engine, TIBEO (Therapeutic Index and Brain Exposure Optimization), has been validated through successful partnerships including with Blueprint Medicines for a brain penetrant EGFR Exon-20 program. The Company's pipeline consists of a first in class dual coREST modifier, JBI-802, currently in a Phase I/II clinical trial in multiple tumors, a novel brain-penetrant modulator of PRMT5 for which an IND has been accepted, brain penetrant and gut restrictive PDL1 inhibitors, as well as PAD4 inhibitors for oncology and inflammatory indications. The Company is headquartered in Bedminster, New Jersey and guided by globally renowned scientific advisors. For more please visit: Twitter @JubilantTx, LinkedIn Logo: SOURCE Jubilant Therapeutics Inc.

高管变更

2023-04-13

·PRNewswire

Jubilant Therapeutics Inc.'s Selective, Orally Administered PAD4 Inhibitor Demonstrates Activity in Rheumatoid Arthritis Preclinical Models

Research conducted in collaboration with Boston Children's Hospital and published in the peer-reviewed journal - Scientific Reports BEDMINSTER, N.J., April 13, 2023 /PRNewswire/ -- Jubilant Therapeutics Inc., a clinical stage biopharmaceutical company advancing small molecule precision therapeutics to address unmet medical needs in oncology and autoimmune diseases, today announced publication of novel research demonstrating that a highly selective, non-competitive and orally administered inhibitor of Protein Arginine Deiminase 4 (PAD4), showed remarkable efficacy in two animal models of Rheumatoid Arthritis (RA). Correlative in vitro studies confirmed that PAD4 inhibition acts by inhibiting NETosis, a fundamental pathophysiological mechanism in the establishment of many autoimmune diseases. The research was conducted in collaboration with Prof. Denisa Wagner a pioneer in PAD4 target space, at the Boston Children's Hospital. The research was published in Scientific Reports (). "We are evaluating several selective, oral PAD4 inhibitors that have emerged from our TIBEO discovery engine for the treatment of both autoimmune diseases and cancer," said Luca Rastelli, Ph.D., Chief Scientific Officer, Jubilant Therapeutics Inc. "Previous research on PAD4 activity and the resulting citrullinated proteins has implicated this target in the genesis of autoimmune diseases, therefore making the development of selective, orally available PAD4 inhibitors a valuable option for patients. The results presented in this paper showed substantial improvement in symptoms, molecular biomarkers and in the bone and tendons damage that result from RA. They also confirmed the underlying mechanism of action building on earlier research on PAD4 inhibition. We are now planning to select a lead PAD4 inhibitor candidate and will be progressing it for IND enabling studies." PAD4 is an enzyme that catalyzes citrullination of proteins and the release of neutrophil extracellular traps (NETs). Its role in autoimmune diseases has been established through clinical genetics and gene knock out studies in mice. This study evaluated an oral, highly selective PAD4 inhibitor, both in vitro and in two RA animal models. In human and mouse neutrophils, PAD4 inhibitor inhibited NET formation, in vitro. In two RA mouse models, JBI-589 reduced several measures of RA and inflammation including joint erosion, RA clinical score and inflammatory markers. About Jubilant Therapeutics Inc. Jubilant Therapeutics Inc. is a clinical stage biopharmaceutical company developing precision oral medicines with enhanced therapeutic index to address unmet medical needs in oncology and autoimmune diseases for genetically defined patients. Its advanced structure based discovery engine, TIBEO (Therapeutic Index and Brain Exposure Optimization), has been validated through successful partnerships including with Blueprint Medicines for a brain penetrant EGFR Exon-20 program. The Company's pipeline consists of a first in class dual coREST modifier, JBI-802, currently in a Phase I/II clinical trial in multiple tumors, a novel brain-penetrant modulator of PRMT5 for which an IND has been accepted, brain penetrant and gut restrictive PDL1 inhibitors, as well as PAD4 inhibitors for oncology and inflammatory indications. The Company is headquartered in Bedminster, New Jersey and guided by globally renowned scientific advisors. For more please visit: Twitter @JubilantTx, LinkedIn Logo: SOURCE Jubilant Therapeutics Inc.

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适应症	最高研发状态	国家/地区	公司	日期
化脓性汗腺炎	临床前	美国	Jubilant Therapeutics, Inc.初创企业	2022-10-12
肝转移	临床前	美国	Jubilant Therapeutics, Inc.初创企业	2022-10-12
类风湿关节炎	临床前	美国	Jubilant Therapeutics, Inc.初创企业	2022-10-12
血管炎	临床前	美国	Jubilant Therapeutics, Inc.初创企业	2022-10-12