Novel RORgamma antagonists for inflammation and autoimmune disease

用于治疗炎症和自身免疫性疾病的新型 RORgamma 拮抗剂

• 批准号: 8632749
• 负责人: Adel Nefzi
• 金额: $ 75.2万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632749
• 关键词: Affect; Agonist; Animal Model; Attenuated; Autoimmune Diseases; Bacterial Infections; Binding; Biochemical; Biological Assay; Biological Factors; Cell Differentiation process; Cell model; Cell physiology; Cells; Cellular Assay; Chemicals; Cholesterol; Clinic; Clinical; Collection; Computer Assisted; Cosmetics; Coupled; Development; Digoxin; Disease; Drug Design; Estrogen Receptors; Experimental Autoimmune Encephalomyelitis; Family; Genetic; Glucocorticoid Receptor; Goals; Heart Diseases; Host Defense; Human; Hydroxycholesterols; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Institutes; Insulin-Dependent Diabetes Mellitus; Interleukin-17; Lead; Length; Libraries; Ligand Binding; Ligand Binding Domain; Ligands; Liver; Measurement; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Nuclear Hormone Receptors; Onset of illness; Orphan; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plants; Production; Protein Isoforms; Psoriasis; Reporting; Research; Resources; Retinoids; Rheumatoid Arthritis; Risk; Role; Safety; Scanning; Series; Source; Structure; Structure-Activity Relationship; Therapeutic; Thymus Gland; Time; Uterine Cancer; analog; anticancer activity; base; combinatorial; comparative efficacy; computer studies; cytokine; cytotoxicity; experience; high throughput screening; imidazolone; improved; in vivo; inhibitor/antagonist; innovation; interest; interleukin-22; malignant breast neoplasm; member; mouse model; novel; prevent; public health relevance; receptor; scaffold; screening; small molecule; small molecule libraries; transcription factor; ursolic acid

DESCRIPTION (provided by applicant): A growing body of evidence suggests a pathogenic role for pro-inflammatory T helper 17 cells (Th17) in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type I diabetes, and psoriasis - diseases for which no curative treatment is currently available. Differentiated Th17 cells are characterized by the production of pro-inflammatory cytokines including IL-17A (IL-17), IL-17F, IL-21, and IL-22. Two members of the Retinoid-related Orphan Receptor (ROR) subfamily of Nuclear Hormone Receptors have been identified as key regulators of Th17 differentiation: RORgammat (a thymus-specific isoform of RORgamma with identical Ligand Binding Domain) and RORalpha. Targeting Th17 cell differentiation by inhibiting RORgammat and/or RORalpha has thus become an attractive strategy for potential treatment of inflammatory autoimmune diseases. Fine tuning inhibition of these two receptors may be desirable to minimize safety risks, as IL-17 is important for controlling host defenses against bacterial infections and complete elimination of IL-17 could be associated with increased risk of infection. RORs have been orphan receptors until very recently. Once the crystal structure of RORalpha revealed the presence of cholesterol in the ligand binding pocket, biochemical and structural studies established that hydroxycholesterols function as natural ligands for RORgamma. In addition, two natural products (digoxin and ursolic acid) and one synthetic molecule (SR1001), which were found to function as RORgamma antagonists, are effective in suppressing Th17 differentiation and delaying the onset of disease in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This proves the efficacy of RORgamma inhibitors as a potential therapeutic strategy for autoimmune diseases, and encourages further research to discover novel compounds with enhanced potency and selectivity that could offer better clinical alternatives. We have identified novel chemical entities that function as RORgamma antagonists from Mixture-based Synthetic Combinatorial Libraries. Our goals are i) to evaluate the effect of our lead compounds in Th17 cell differentiation and autoimmune disease in mice; ii) to further deconvolute active mixtures following a cell-based screening platform to identify novel negative modulators of RORgamma activity; iii) to establish how the ROR- selectivity profile of these novel RORgamma inhibitors affects Th17 differentiation and autoimmune disease; and iv) to optimize leads following a structure-based approach to improve their potency and RORgamma selectivity. TPIMS mixture-based chemical libraries are unique and offer an excellent source for innovative RORgamma ligands. Based on our preliminary studies and our experience with this type of chemical libraries, we are confident that this proposal will produce novel potent RORgamma antagonists that will prove effective in preventing Th17 cell differentiation and delaying the onset and/or ameliorating autoimmune disease in mice. These compounds will offer an exceptional opportunity for the development of innovative RORgamma-based therapeutics against inflammatory autoimmune diseases.

描述（由申请人提供）：越来越多的证据表明促炎性T辅助细胞17（Th 17）在几种自身免疫性疾病中的致病作用，包括多发性硬化症、类风湿性关节炎、炎症性肠病、I型糖尿病和银屑病-目前没有治愈性治疗的疾病。分化的Th 17细胞的特征在于产生促炎细胞因子，包括IL-17 A（IL-17）、IL-17 F、IL-21和IL-22。核激素受体的类视黄醇相关孤儿受体（ROR）亚家族的两个成员已被鉴定为Th 17分化的关键调节因子：ROR γ mat（具有相同配体结合结构域的ROR γ的胸腺特异性同种型）和ROR α。因此，通过抑制ROR γ和/或ROR α靶向Th 17细胞分化已成为潜在治疗炎性自身免疫性疾病的有吸引力的策略。这两种受体的微调抑制可能是理想的，以最大限度地减少安全风险，因为IL-17对于控制宿主对细菌感染的防御是重要的，并且IL-17的完全消除可能与感染风险增加相关。ROR直到最近才成为孤儿受体。一旦ROR α的晶体结构揭示了胆固醇在配体结合口袋中的存在，生物化学和结构研究就确定了羟基胆固醇作为ROR γ的天然配体发挥作用。此外，两种天然产物（地高辛和熊果酸）和一种合成分子（SR 1001），被发现作为ROR γ拮抗剂，在抑制Th 17分化和延迟多发性硬化症的实验性自身免疫性脑脊髓炎小鼠模型中的疾病发作是有效的。这证明了ROR γ抑制剂作为自身免疫性疾病的潜在治疗策略的功效，并鼓励进一步研究以发现具有增强效力和选择性的新型化合物，从而提供更好的临床替代方案。 我们已经从基于混合物的合成组合文库中鉴定了用作ROR γ拮抗剂的新型化学实体。我们的目标是i）评估我们的先导化合物在小鼠中的Th 17细胞分化和自身免疫性疾病中的作用; ii）在基于细胞的筛选平台之后进一步去卷积活性混合物以鉴定新的ROR γ活性负调节剂; iii）确定这些新的ROR γ抑制剂的ROR选择性概况如何影响Th 17分化和自身免疫性疾病;和iv）按照基于结构的方法优化先导物以提高其效力和ROR γ选择性。 TPIMS基于混合物的化学库是独一无二的，为创新ROR γ配体提供了绝佳的来源。基于我们的初步研究和我们对这种类型的化学文库的经验，我们相信该提议将产生新的有效的ROR γ拮抗剂，其将被证明在预防Th 17细胞分化和延迟小鼠中自身免疫性疾病的发作和/或改善小鼠中自身免疫性疾病中是有效的。这些化合物将为开发针对炎症性自身免疫性疾病的基于ROR γ的创新疗法提供绝佳的机会。