Blocking a novel cytokine signaling pathway for the treatment of rheumatoid arthr

阻断新的细胞因子信号通路治疗类风湿关节炎

• 批准号: 8781081
• 负责人: Kirill Ostanin
• 金额: $ 74.72万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781081
• 关键词: Achievement; Acute Lung Injury; Affect; Age related macular degeneration; American; Animal Model; Arthritis; Autoimmune Diseases; Back; Bioavailable; Biochemical Process; Biological Assay; Biological Availability; Blood; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Caring; Cell model; Cells; Chemicals; Chronic; Clinical Chemistry Tests; Clinical assessments; Collagen; Collagen Arthritis; Communicable Diseases; Cytokine Network Pathway; Cytokine Signaling; Development; Dose; Drug Formulations; Drug Kinetics; Employee Strikes; Enzymes; Etanercept; Evaluation; Exhibits; Failure; Functional disorder; Funding; Goals; Gold; Guidelines; Half-Life; Hepatitis; Hour; Immune; Immune response; Immunosuppression; In Vitro; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammation Process; Inflammatory; Interleukin-1; Interleukin-6; Intravenous; Joints; Lead; Left; Leukocytes; Liquid substance; Lung diseases; Marketing; Mediating; Metabolic; Metabolic Clearance Rate; Modeling; Monomeric GTP-Binding Proteins; Mus; Nature; Opportunistic Infections; Oral; Outcome; P-Glycoprotein; Pathogenesis; Pathologic Neovascularization; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Plasma Proteins; Play; Population; Potassium Channel; Pristane; Production; Protein Binding; Rattus; Rheumatoid Arthritis; Risk; Rodent Model; Role; Route; Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Solubility; Staging; Stimulus; Symptoms; TNF gene; Therapeutic; TimeLine; Tissues; Toxicology; Treatment Cost; Treatment Efficacy; Tuberculosis; Validation; angiogenesis; articular cartilage; base; bone; commercialization; cytokine; cytotoxicity; drug candidate; drug development; drug discovery; efflux pump; high risk; improved; in vitro Model; in vivo; in vivo Model; infliximab; inhibitor/antagonist; joint destruction; lead series; method development; mouse model; non-compliance; novel; novel therapeutics; pre-clinical; process optimization; programs; public health relevance; receptor; response; small molecule; subcutaneous; treatment strategy; tumor

DESCRIPTION (provided by applicant): In spite of remarkable progress in management of rheumatoid arthritis (RA), a devastating autoimmune disease that affects 2.5 million Americans causing chronic inflammation of joints and surrounding tissues, the gap of unmet needs in this therapeutic field remains wide open. First of all, almost 50% of the patients do not respond adequately to the most advanced mainstay treatment with the biologics, such as Remicade and Enbrel, that target individual pro-inflammatory cytokines. It is recognized that these therapeutic failures may be related to the functional redundancies within the cytokine network. Furthermore, the current RA medications act by suppressing multiple axes of immune response thereby markedly elevating risk of opportunistic infections. Both the relatively high cost of treatment and invasive (intravenous, subcutaneous or intra-articular) route of administration also contribute to the list of notable drawbacks for the standard-of-care RA biologics. A potential new strategy for the treatment of rheumatoid arthritis, which centers on maintaining vascular integrity with minimal overall immunosuppression, provides the rationale for the present project. The essential roles of vascular response in RA pathophysiology are well documented. Both disruption of vascular endothelial barrier and pathologic angiogenesis that are induced by pro-inflammatory stimuli including cytokines in synovial tissue play key roles in rheumatoid inflammation and destruction of joints. Our proposed signaling model suggests that inhibitors of small GTPase Arf6 would block vascular hyperpermeability and angiogenesis at a convergence point downstream from multiple "pro-arthritic" receptors while leaving the NF?B cascade, which governs other aspects of immune response, essentially intact. In our view, such a therapeutic approach may allow, first, to improve responsiveness to the treatment by overcoming the limitation associated with cytokine redundancies, and, second, to improve drug safety by minimizing immunosuppressive effects. The first in-class chemical series of small molecule Arf6 inhibitors identified in the Phase I SBIR study is proposed as a starting point for the medicinal chemistry-driven lead optimization program in Phase II. Its top representatives have been characterized by both cell barrier-stabilizing and anti-angiogenic activities in cellular models and, most importantly, by therapeutic efficacy comparable to that of Enbrel in a mouse model of collagen-induced arthritis. The proposed efforts are projected to yield orally bioavailable candidates for pre- clinical IND enabling studies with appropriate pharmacokinetic and toxicology profiles. The pharmacological modulation of Arf6 function may also have therapeutic potential in the context of other indications associated with vascular leak as evidenced by the promising outcome of preliminary efficacy studies using in vivo models of wet age-related macular degeneration and inflammation-induced acute lung injury.

描述（由申请人提供）：类风湿关节炎（RA）是一种毁灭性的自身免疫性疾病，影响着250万美国人的关节和周围组织的慢性炎症，尽管在类风湿关节炎（RA）的治疗方面取得了显著进展，但这一治疗领域未满足需求的缺口仍然很大。首先，几乎50%的患者对最先进的生物制剂（如Remicade和Enbrel）的主流治疗没有充分的反应，这些生物制剂针对个体促炎细胞因子。人们认识到，这些治疗失败可能与细胞因子网络中的功能冗余有关。此外，目前的类风湿性关节炎药物通过抑制免疫反应的多个轴，从而显着增加机会性感染的风险。相对较高的治疗费用和