Novel therapeutic target to combat cutaneous lupus

对抗皮肤狼疮的新治疗靶点

• 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
• 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

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.

项目摘要/摘要：皮肤红斑狼疮等慢性自身炎症性皮肤病