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: 9228916
• 负责人: Adel Nefzi
• 金额: $ 58.44万
• 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/9228916
• 关键词: Affect; Agonist; Alpha Cell; Attenuated; Autoimmune Diseases; Bacterial Infections; Binding; Biochemical; Biological Assay; Cell Differentiation process; Cell model; Cell physiology; Cells; Cellular Assay; Chemicals; Cholesterol; Clinic; Clinical; Collection; Computer Assisted; Cosmetics; Coupled; Crystallization; Development; Digoxin; Disease; Drug Design; Estrogen Receptors; Experimental Animal Model; Experimental Autoimmune Encephalomyelitis; Family; Genetic study; 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 X Receptor; Measurement; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Natural Products; Nuclear Hormone Receptors; Onset of illness; Orphan; Pathogenicity; 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; curative treatments; 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 细胞 (Th17) 在多种自身免疫性疾病中具有致病作用，包括多发性硬化症、类风湿性关节炎、炎症性肠病、I 型糖尿病和牛皮癣，这些疾病目前尚无治愈方法。分化的 Th17 细胞的特点是产生促炎细胞因子，包括 IL-17A (IL-17)、IL-17F、IL-21 和 IL-22。核激素受体的视黄醇相关孤儿受体 (ROR) 亚家族的两个成员已被确定为 Th17 分化的关键调节因子：RORgammat（具有相同配体结合域的胸腺特异性 RORgamma 亚型）和 RORalpha。因此，通过抑制 RORγ 和/或 RORα 来靶向 Th17 细胞分化已成为潜在治疗炎症性自身免疫性疾病的一种有吸引力的策略。对这两种受体进行微调抑制可能有助于最大程度地降低安全风险，因为 IL-17 对于控制宿主对细菌感染的防御非常重要，并且完全消除 IL-17 可能与感染风险增加有关。直到最近，ROR 一直是孤儿受体。一旦 RORalpha 的晶体结构揭示了配体结合袋中存在胆固醇，生化和结构研究就确定羟基胆固醇可作为 RORgamma 的天然配体。此外，两种天然产物（地高辛和熊果酸）和一种合成分子（SR1001）被发现具有 RORgamma 拮抗剂的作用，可有效抑制多发性硬化症实验性自身免疫性脑脊髓炎小鼠模型中的 Th17 分化并延缓疾病的发作。这证明了 RORgamma 抑制剂作为自身免疫性疾病潜在治疗策略的功效，并鼓励进一步研究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。 我们从基于混合物的合成组合文库中鉴定出了充当 RORgamma 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对小鼠 Th17 细胞分化和自身免疫性疾病的影响； ii) 根据基于细胞的筛选平台进一步对活性混合物进行解卷积，以识别 RORgamma 活性的新型负调节剂； iii) 确定这些新型 RORgamma 抑制剂的 ROR 选择性特征如何影响 Th17 分化和自身免疫性疾病； iv) 按照基于结构的方法优化先导化合物，以提高其效力和 RORgamma 选择性。 基于 TPIMS 混合物的化学库是独一无二的，为创新的 RORgamma 配体提供了极好的来源。根据我们的初步研究和我们在此类化学文库方面的经验，我们相信该提案将产生新型有效的 RORgamma 拮抗剂，这些拮抗剂将被证明可有效预防 Th17 细胞分化并延迟发病和/或改善小鼠自身免疫性疾病。这些化合物将为开发基于 RORgamma 的创新疗法对抗炎症性自身免疫性疾病提供绝佳的机会。