Novel RORgamma antagonists for inflammation and autoimmune disease

描述(申请人提供)：越来越多的证据表明，促炎T辅助17细胞(Th17)在几种自身免疫性疾病中起致病作用，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--这些疾病目前尚无根治疗法。分化的Th17细胞的特征是产生促炎细胞因子，包括IL-17A(IL-17)、IL-17F、IL-21和IL-22。视黄醇相关孤儿受体(ROR)核激素受体亚家族中的两个成员被确定为Th17分化的关键调节因子：RORGammat(具有相同配体结合结构域的胸腺特异的RORGammat)和RORpha。因此，通过抑制RORGammat和/或RORpha靶向Th17细胞分化已成为治疗炎症性自身免疫性疾病的一种有吸引力的策略。微调抑制这两种受体可能是可取的，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，完全消除IL-17可能与感染风险增加相关。直到最近，RORS一直是孤立的受体。一旦RORpha的晶体结构揭示了配体结合口袋中存在胆固醇，生物化学和结构研究就证实了羟基胆固醇是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拮抗剂的功能，在多发性硬化症的实验性自身免疫性脑脊髓炎小鼠模型中，它们在抑制Th17分化和延迟疾病发病方面是有效的。这证明了RORGamma抑制剂作为一种潜在的自身免疫性疾病治疗策略的有效性，并鼓励进一步研究，以发现具有更强效力和选择性的新化合物，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库中鉴定了作为RORGamma拮抗剂的新化学实体。我们的目标是：i)评估我们的先导化合物在Th17细胞分化和小鼠自身免疫性疾病中的作用；ii)根据细胞筛选平台进一步拆解活性混合物，以确定新型RORGamma活性的负调节因子；iii)确定这些新型RORGamma抑制剂的ROR选择性谱如何影响Th17细胞分化和自身免疫性疾病；以及iv)遵循基于结构的方法优化先导化合物，以提高它们的效力和RORGamma选择性。TPIMS基于混合物的化学库是独一无二的，为创新的RORGamma配体提供了一个极好的来源。根据我们的初步研究和我们在这类化学库方面的经验，我们相信这项提议将产生新的有效的RORGamma拮抗剂，将被证明在防止Th17细胞分化、延迟和/或改善小鼠自身免疫性疾病方面有效。这些化合物将为开发基于RORGamma的抗炎症性自身免疫性疾病的创新疗法提供一个难得的机会。

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.