Novel therapeutic target to combat cutaneous lupus

对抗皮肤狼疮的新治疗靶点

基本信息

批准号：
10255592
负责人：
Fanny Astruc Diaz
金额：
$ 29.81万
依托单位：
DERMAXON, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255592
关键词：
AKT1 gene Acids Address Adult Affect American Anti-Inflammatory Agents Autoantibodies Autoimmune Diseases Binding Biochemistry Blood CCL3 gene CXCL10 gene CXCL9 gene Cells Chemicals Chronic Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Cutaneous Cutaneous Lupus Erythematosus Data Dendritic Cells Dependence Dermal Dermatitis Dermatology Disease Dose Ensure Epidermis Equilibrium Event Exhibits Exposure to FDA approved Family Gene Expression Genes Goals Half-Life Histologic Homology Modeling Human IL8 gene Immune Immunology In Vitro Inflammation Inflammatory Interferon Receptor Interferon Type I Interferon Type II Interferons Interleukin-6 KDR gene Knock-out Laboratories Lead Lesion Ligands Liver Microsomes Mammalian Cell Measures Metabolic Molecular Montana Nucleic Acids Open Reading Frames PLK1 gene Pathology Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Phosphotransferases Production Property Protein Kinase Proteins Regulation Reporting Research Proposals Role SYK gene Safety Series Signal Transduction Signaling Protein Skin Small Business Technology Transfer Research Small Interfering RNA Systemic Lupus Erythematosus Systemic Therapy TLR3 gene Testing Therapeutic Topical application Toxic effect Toxicology Treatment Protocols Universities Viral Genes Work analog aurora kinase A autoinflammation autoinflammatory base chemokine combat cytokine design druggable target effective therapy efficacy testing experimental study humanized monoclonal antibodies improved inhibitor/antagonist keratinocyte kinase inhibitor knock-down lupus cutaneous mRNA Expression member metabolic abnormality assessment new therapeutic target next generation novel novel therapeutics nucleic acid binding protein pathogen patient tolerability pediatric patients preclinical study professor protein expression public health relevance receptor recruit response skin disorder skin lesion small molecule virtual screening

项目摘要

Project Summary / Abstract: Chronic auto-inflammatory skin diseases such as cutaneous lupus erythematosus (CLE) affect millions of Americans with limited therapeutic options currently available, creating a significant need for novel therapeutic options. A hallmark of CLE is the presence of autoantibodies against nucleic acids and nucleic acid-binding proteins, as well as elevated interferons (IFNs). In CLE it remains unclear which mechanisms are most critical in precipitating disease; however, CLE lesions histologically present as an interface dermatitis, which is orchestrated by type-I and type III interferons and interferon-regulated chemokines largely produced by basal keratinocytes in the lower epidermis. Importantly, a break-through discovery in our laboratories has identified a novel kinase target for the inhibition of type-I and type-III IFN production called RIOK3. RIOK3 is a member of the RIO protein kinase family (right open reading frame kinase) and preliminary data from CRISPR knockout and siRNA knockdowns in mammalian cells demonstrates its prominent role in IFN production. Following knockout studies, we tested two compounds that are able to bind RIOK3. They significantly decreased Type I and III IFN mRNA and protein expression following keratinocyte exposure to polyriboinosinic- polyribocytidylic acid (polyI:C or PIC), a TLR3 ligand that activates interferon pathways. Additionally, media transfer experiments in keratinocytes confirm that RIOK3 inhibition not only reduces the IFN response in PIC exposed cells but also disrupts the IFN feed-forward loop, as measured by IFN-regulated protein CXCL10, a key driver of immune cell hyper-recruitment to the skin in CLE lesions. This preliminary work strongly supports our central hypothesis that a topical RIOK3 inhibitor will dose-dependently decrease cutaneous IFNs and IFN- regulated genes, resulting in the reduction of CLE lesions, with improved efficacy and patient tolerance compared to systemic treatments. Importantly, unlike JAK inhibitors that have an ON/OFF effect on many cellular pathways, a topical RIOK3 inhibitor could work selectively and dose-dependently to finely regulate IFN secretion and restore IFN balance in the skin. Therefore, RIOK3 inhibitors hold immense potential as a novel class of next generation kinase inhibitors. The research proposal has two principal aims: In SA1, we will complete the characterization of a defined series of previously identified, but promiscuous, RIOK3 inhibitors on Type I and Type III IFNs in keratinocytes. This will inform SAR-based selection and optimization of the most active chemical moieties. These compounds will be designed for topical delivery and will be assessed for RIOK3 activity and selectivity. In SA2, we will establish the efficacy of our top three candidates in stimulated reconstructed human epidermis. Top candidates will pass skin toxicological studies and will undergo metabolism studies to ensure effective skin half- life with low blood half-life. The overall goal of this collaborative effort between experts in medicinal chemistry, immunology, and dermatology is to demonstrate the incredible potential of RIOK3 selective inhibitors as a first- in-class, novel kinase inhibitor for treatment of adult and pediatric patients suffering from CLE.

项目概要/摘要：皮肤红斑狼疮等慢性自身炎症性皮肤病（CLE）影响着数百万美国人，目前可用的治疗选择有限，产生了巨大的需求寻找新的治疗选择。 CLE 的一个标志是存在针对核酸的自身抗体和核酸结合蛋白，以及升高的干扰素 (IFN)。在 CLE 中，目前还不清楚哪个机制对于引发疾病最为关键；然而，CLE 病变在组织学上表现为界面皮炎，主要由 I 型和 III 型干扰素以及干扰素调节的趋化因子精心策划由下表皮的基底角质形成细胞产生。重要的是，我们的突破性发现实验室已经确定了一种新的激酶靶点，用于抑制 I 型和 III 型干扰素的产生，称为 RIOK3。 RIOK3是RIO蛋白激酶家族（右开放阅读框激酶）的成员，初步哺乳动物细胞中 CRISPR 敲除和 siRNA 敲除的数据证明了其在 IFN 中的突出作用生产。在敲除研究之后，我们测试了两种能够结合 RIOK3 的化合物。他们显着地角质形成细胞暴露于聚核糖肌苷后，I 型和 III 型 IFN mRNA 和蛋白质表达降低聚核糖胞苷酸（polyI:C 或 PIC），一种激活干扰素通路的 TLR3 配体。此外，媒体角质形成细胞中的转移实验证实，RIOK3 抑制不仅降低了 PIC 中的 IFN 反应暴露的细胞，但也会破坏 IFN 前馈环路，如 IFN 调节蛋白 CXCL10 所测量，CXCL10 是一种关键的干扰素调节蛋白。 CLE 病变中免疫细胞向皮肤过度募集的驱动因素。这项前期工作有力地支持了我们中心假设是局部 RIOK3 抑制剂会剂量依赖性地减少皮肤 IFN 和 IFN- 调节基因，导致 CLE 病变减少，与相比，疗效和患者耐受性提高到系统治疗。重要的是，与对许多细胞途径具有开/关作用的 JAK 抑制剂不同，局部 RIOK3 抑制剂可以选择性地、剂量依赖性地发挥作用，精细调节 IFN 分泌并恢复皮肤中的干扰素平衡。因此，RIOK3抑制剂作为下一代新型抑制剂具有巨大的潜力激酶抑制剂。该研究计划有两个主要目标：在 SA1 中，我们将完成一系列先前确定的但混杂的 RIOK3 抑制剂，作用于 I 型和 III 型干扰素角质形成细胞。这将为基于 SAR 的最活跃化学部分的选择和优化提供信息。这些化合物将被设计用于局部给药，并将评估 RIOK3 活性和选择性。在SA2中，我们将确定我们的三大候选药物在刺激重建人类表皮中的功效。顶部候选人将通过皮肤毒理学研究，并将进行新陈代谢研究，以确保有效的皮肤半血液半衰期低的生命。药物化学专家之间合作的总体目标，免疫学和皮肤病学的目的是证明 RIOK3 选择性抑制剂作为第一种药物的令人难以置信的潜力用于治疗患有 CLE 的成人和儿童患者的同类新型激酶抑制剂。