Ubiquitin E3 ligase activators for treatment of psoriasis

泛素 E3 连接酶激活剂用于治疗牛皮癣

基本信息

批准号：
9770061
负责人：
Kumar Suresh
金额：
$ 22.45万
依托单位：
PROGENRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9770061
关键词：
Ablation Adaptive Immune System Adaptor Signaling Protein Adrenal Cortex Hormones Affect Animal Model Antibodies Asthma Biological Biological Availability Biological Response Modifier Therapy Biological Response Modifiers Blocking Antibodies Cardiovascular Diseases Cell Differentiation process Cell Survival Cells Chemicals Chronic Chronic small plaque psoriasis Colitis Comorbidity Data Development Disease Disease model Drug Kinetics Exhibits FDA approved Family Genetic Goals Human Imiquimod Immune Immune System Diseases Immune system Immunosuppressive Agents Impairment Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin-1 Interleukin-17 Interleukin-6 Joints Knock-out Laboratories Lead Ligase Lymphoid Cell Malignant Neoplasms Mediating Microsomes Modeling Mus Oral Pathology Pathway interactions Patients Phase Plasma Production Proteins Pruritus Psoriasis Psoriatic Arthritis Quality of life Recurrent disease Research Personnel Safety Signal Transduction Skin T-Lymphocyte TNF gene Therapeutic Treatment Efficacy Ubiquitin Ubiquitination adalimumab clinically relevant cost cytokine drug development drug discovery efficacy evaluation enzyme pathway immune function improved in vivo in vivo Model innovation keratinocyte lead optimization macrophage multicatalytic endopeptidase complex neutrophil novel peripheral blood preclinical evaluation protein degradation proteostasis scaffold side effect small molecule symptom treatment targeted treatment therapeutic target transcription factor ubiquitin-protein ligase

项目摘要

Psoriasis is a chronic, uncurable multisystem inflammatory disease affecting skin and joints and leading to numerous complications. Symptomatic relief is available, but treatments, including biologicals, are compromised by safety and other issues, suggesting a need for improved therapies. Psoriasis is driven by immune cell-derived proinflammatory cytokines that cause uncontrolled keratinocyte proliferation; these cytokines can be induced by TNF, and TNF blocking antibodies such as adalimumab are approved for chronic plaque psoriasis. In addition, T helper (Th)17 cells produce IL-17A and IL-17F, which also activate keratinocyte proliferation. Accordingly, the anti-IL17A antibody secukinumab is approved for psoriasis. Thus, suppression of TH17 differentiation and/or IL- 17 signaling is a validated therapeutic approach for treating the underlying causes of psoriasis. The ubiquitin proteasome pathway is a primary regulator of immune function; the Nedd4-family E3 ligase Itch, which negatively regulates inflammatory responses, is a validated target for inflammation. Genetic ablation of Itch leads to multisystem immune disorders. The ligase is normally autoinhibited but is activated by the adapter protein Ndfip1. Ndfip1-/- mice develop inflammatory disease similarly to Itch-/- mice. Recently, Dr. Venuprasad Poojary’s laboratory discovered that Itch causes proteasomal degradation of the lineage specific transcription factor ROR- γT, thereby suppressing Th17 differentiation and IL-17 production. Itch-/- mice develop spontaneous colitis and exhibit elevated IL-17 levels. Thus, Itch is a master negative regulator of inflammatory responses and its activation should provide therapeutic benefit. Progenra recently discovered small molecule Itch activators, and subsequent lead optimization has identified distinct chemical scaffolds (P053506 and P243876) that selectively activate Itch and impair cytokine production by T-cells. Moreover, they suppress IL-17 mRNAlevels in Th17 cells. It is proposed here to develop small molecule Itch activators as oral agents to limit TH17 differentiation and cytokine production, ultimately dampening the inflammatory responses in in vivo models of psoriasis and potentially having utility to treat severe to moderate psoriasis. In Phase I, the effect of selective Itch activators on Th17 cell differentiation, IL-17 production, and ROR-T protein levels will be determined, and candidate activators will be evaluated for pharmacokinetics and oral bioavailability. The Imiquimod induced murine psoriasis model will be employed to determine in vivo efficacy. In Phase II, lead development and preclinical evaluation will continue using clinically relevant animal models. A successful project will lead to novel small molecule agents that can be used alone or in combination to treat psoriasis and other inflammatory diseases.

牛皮癣是一种慢性、无法治愈的多系统炎症性疾病，影响皮肤和关节，并导致许多并发症可以缓解，但治疗方法（包括生物制剂）却受到影响。由于安全性和其他问题，表明需要改进的治疗方法是由免疫细胞衍生的。导致角质形成细胞增殖失控的促炎细胞因子；这些细胞因子可以由以下因素诱导： TNF 和 TNF 阻断抗体（例如阿达木单抗）被批准用于治疗慢性斑块型银屑病。 T 辅助细胞 (Th)17 产生 IL-17A 和 IL-17F，它们也会激活角质形成细胞增殖。抗 IL17A 抗体苏金单抗被批准用于治疗牛皮癣，从而抑制 TH17 分化和/或 IL-17。 17 信号传导是一种经过验证的治疗方法，用于治疗牛皮癣的根本原因。蛋白酶体途径是免疫功能的主要调节因子；Nedd4 家族 E3 连接酶 Itch 对免疫功能产生负面影响；调节炎症反应，是炎症基因消除的有效靶标。连接酶通常是自抑制的，但会被接头蛋白 Ndfip1 激活。最近，Venuprasad Poojary 博士的研究表明，Ndfip1-/- 小鼠会出现与 Itch-/- 小鼠相似的炎症性疾病。实验室发现 Itch 会导致谱系特异性转录因子 ROR- 的蛋白酶体降解 γT，从而抑制 Th17 分化和 IL-17 产生，Itch-/- 小鼠出现自发性结肠炎和表现出升高的 IL-17 水平，因此，Itch 是炎症反应及其炎症反应的主要负调节因子。 Progenra 最近发现了小分子瘙痒激活剂，并且应该具有治疗作用。随后的先导化合物优化已确定了不同的化学支架（P053506 和 P243876），它们选择性地激活瘙痒并损害 T 细胞产生细胞因子，此外，它们还能抑制 Th17 细胞中的 IL-17 mRNA 水平。这里建议开发小分子瘙痒激活剂作为口服制剂来限制 TH17 分化和细胞因子的产生，最终抑制牛皮癣体内模型的炎症反应在第一阶段，选择性瘙痒激活剂的作用可能有助于治疗重度至中度牛皮癣。将确定 Th17 细胞分化、IL-17 产生和 ROR-T 蛋白水平的影响，并候选将评估咪喹莫特诱导小鼠的药代动力学和口服生物利用度。银屑病模型将用于确定第二阶段的体内疗效、先导药物开发和临床前研究。评估将继续使用临床相关的动物模型。一个成功的项目将产生新的小型动物。可以单独或联合使用来治疗牛皮癣和其他炎症性疾病的分子药物。