Ubiquitin E3 ligase activators for treatment of psoriasis

银屑病是一种慢性、不可治愈的多系统炎症性疾病，影响皮肤和关节，并导致 无数的并发症。症状缓解是可行的，但包括生物制品在内的治疗方法是有问题的 安全性和其他问题，表明需要改进治疗方法。牛皮癣是由免疫细胞衍生的 导致角质形成细胞不受控制的增殖的促炎细胞因子；这些细胞因子可以通过以下方式诱导 肿瘤坏死因子和肿瘤坏死因子阻断抗体，如阿达利单抗，被批准用于治疗慢性斑块型银屑病。此外, 辅助性T细胞(Th)17细胞产生IL-17A和IL-17F，也激活角质形成细胞的增殖。因此， 抗IL17A抗体Suckinumab被批准用于治疗牛皮癣。因此，抑制Th17分化和/或IL- 17信号转导是治疗银屑病根本原因的有效治疗方法。无所不在的 蛋白酶体途径是免疫功能的主要调节因子；Nedd4家族E3连接酶瘙痒 调节炎症反应，是炎症的有效靶点。遗传消融瘙痒导致 多系统免疫紊乱。连接酶通常是自动抑制的，但被适配蛋白Ndfip1激活。 Ndfip1-/-小鼠患炎症性疾病与瘙痒-/-小鼠相似。最近，Venuprasad Poojary博士的 实验室发现，瘙痒会导致谱系特异性转录因子ROR的蛋白酶体降解。 γT，从而抑制Th17的分化和IL-17的产生。瘙痒/-小鼠发生自发性结肠炎和 表现出IL-17水平升高。因此，Itch是炎症反应的主要负调节因子，其 激活应该能提供治疗益处。Progenra最近发现了小分子瘙痒激活剂，以及 随后的铅优化确定了不同的化学支架(P053506和P243876)，它们选择性地 激活瘙痒并抑制T细胞产生细胞因子。此外，它们还抑制Th17细胞中IL-17mRNAs的水平。 建议开发小分子瘙痒激活剂作为口服药物，以限制TH17的分化和 细胞因子的产生，最终抑制银屑病体内模型的炎症反应 对治疗重度至中度牛皮癣有潜在的效用。在第一阶段，选择性瘙痒激活剂的效果 对Th17细胞分化、IL-17产生和RoR-T蛋白水平进行测定，候选 将评估激活剂的药代动力学和口服生物利用度。咪喹莫特诱导的小鼠 将采用银屑病模型进行体内疗效判定。在第二阶段，Lead开发和临床前 评估将继续使用临床相关的动物模型。一个成功的项目将带来新奇的小 可单独或联合用于治疗牛皮癣和其他炎症性疾病的分子制剂。

Psoriasis is a chronic, uncurable multisystem inflammatory disease affecting skin and joints and leading to numerous complications. Symptomatic relief is available, but treatments, including biologicals, are compromised by safety and other issues, suggesting a need for improved therapies. Psoriasis is driven by immune cell-derived proinflammatory cytokines that cause uncontrolled keratinocyte proliferation; these cytokines can be induced by TNF, and TNF blocking antibodies such as adalimumab are approved for chronic plaque psoriasis. In addition, T helper (Th)17 cells produce IL-17A and IL-17F, which also activate keratinocyte proliferation. Accordingly, the anti-IL17A antibody secukinumab is approved for psoriasis. Thus, suppression of TH17 differentiation and/or IL- 17 signaling is a validated therapeutic approach for treating the underlying causes of psoriasis. The ubiquitin proteasome pathway is a primary regulator of immune function; the Nedd4-family E3 ligase Itch, which negatively regulates inflammatory responses, is a validated target for inflammation. Genetic ablation of Itch leads to multisystem immune disorders. The ligase is normally autoinhibited but is activated by the adapter protein Ndfip1. Ndfip1-/- mice develop inflammatory disease similarly to Itch-/- mice. Recently, Dr. Venuprasad Poojary’s laboratory discovered that Itch causes proteasomal degradation of the lineage specific transcription factor ROR- γT, thereby suppressing Th17 differentiation and IL-17 production. Itch-/- mice develop spontaneous colitis and exhibit elevated IL-17 levels. Thus, Itch is a master negative regulator of inflammatory responses and its activation should provide therapeutic benefit. Progenra recently discovered small molecule Itch activators, and subsequent lead optimization has identified distinct chemical scaffolds (P053506 and P243876) that selectively activate Itch and impair cytokine production by T-cells. Moreover, they suppress IL-17 mRNAlevels in Th17 cells. It is proposed here to develop small molecule Itch activators as oral agents to limit TH17 differentiation and cytokine production, ultimately dampening the inflammatory responses in in vivo models of psoriasis and potentially having utility to treat severe to moderate psoriasis. In Phase I, the effect of selective Itch activators on Th17 cell differentiation, IL-17 production, and ROR-T protein levels will be determined, and candidate activators will be evaluated for pharmacokinetics and oral bioavailability. The Imiquimod induced murine psoriasis model will be employed to determine in vivo efficacy. In Phase II, lead development and preclinical evaluation will continue using clinically relevant animal models. A successful project will lead to novel small molecule agents that can be used alone or in combination to treat psoriasis and other inflammatory diseases.