Novel small molecule HSP90 inhibitor for the management of atopic dermatitis

项目摘要 特应性皮炎/AD（或"特应性湿疹"）是一种复杂的慢性炎症性皮肤病， 三千五百万美国人AD的特征是表皮屏障功能的破坏， 皮肤瘙痒严重，严重影响患者生活质量。目前的护理标准涉及局部 软化剂，避免触发因子和抗炎策略，包括使用皮质类固醇， 抗组胺药，或广泛的和最近也是特异性的免疫调节剂，如dupilumab。 虽然广泛 免疫抑制疗法可以帮助部分控制疾病，长期使用会导致不良副作用， 影响和药物耐受性，导致患者依从性降低和无效。此外，dupilumab是 在相当一部分患者中无效，表明AD的异质性和个体化治疗的必要性。 基于患者特征的治疗。临床上迫切需要开发靶向的 免疫调节治疗剂，没有免疫抑制副作用， 分析并安全地和选择性地靶向AD的致病介质。HSP90最近被分类为 作为一种"警报"，并在介导先天性和适应性免疫系统之间的相互作用中发挥关键作用。 以及在JAK/STAT和MAP激酶途径以及IL-4、IL-13和IL-17信号传导中的已知作用。这些 通路在AD相关的免疫失调中具有关键作用。雷格拉尼翁最近获得了一部很有影响力的小说 小分子HSP90抑制剂（RGRN-305，以前称为Debio0932）具有良好的安全性和吸引力， 药理学性质，其显示减轻银屑病症状、减少表皮厚度，和 在临床相关动物模型中，TNF α和IL-17、促炎细胞因子水平显著降低 牛皮癣这些研究为正在进行的治疗中度至中度的临床评价奠定了基础。 严重银屑病（ClinicalTrials.gov标识符：NCT 03675542），并为HSP 90的研究设定了优先顺序 作为AD的治疗靶点。本提案的重点是实现将此 作为一种安全有效的口服AD治疗药物的商业化技术， 疾病的蛋白质组介质。本研究的目的包括：（1）严格评价疗效和机制 口服RGRN-305在多个临床相关AD模型中的作用，这些模型包含一项比较疗效研究 相对于皮质类固醇治疗，和ii.）HSP90通路的基因和蛋白表达的表征- 来自中重度AD的正常、非病变和AD病变人皮肤样本中的相关标志物 患者HSP90在AD发病机制和持续性中的作用尚未阐明。鉴于 AD的病因是多方面的，其特征在于表皮HSP90通路的表达谱和相关的 细胞因子和趋化因子将允许洞察治疗潜力和个体化治疗的机会。 RGRN-305治疗。

PROJECT SUMMARY Atopic dermatitis/AD (or ‘atopic eczema’) is a complex, chronic, inflammatory skin disease that affects upwards of 35 million Americans. AD is characterized by a disruption of epidermal-barrier function, inflamed dry and thick skin, severe pruritus and significant impact on patients’ quality of life. Current standard of care involves topical emollients, avoidance of trigger factors and anti-inflammatory strategies including the use of corticosteroids, antihistamines, or broad and recently also specific immunommodulators, such as dupilumab. While broad immunosuppressive therapies can help partly manage the disease, chronic usage results in undesirable side- effects and drug tolerance, resulting in lowered patient compliance and inefficacy. Furthermore, dupilumab is ineffective in a significant portion of patients, suggesting the heterogeneity of AD and need for individualized treatment based on patient profiling. There is a pressing need for the clinical development of targeted immunomodulatory therapeutics, without immunosuppressive side effects, designed to take into account patient profiling and to safely and selectively target pathogenic mediators of AD. HSP90 has been recently classified as an ‘alarmin’ and has key roles in mediating the interplay between the innate and the adaptive immune system as well as known roles in the JAK/STAT and MAP kinase pathway and IL-4, IL-13, and IL-17 signaling. These pathways have key roles in AD-related immune dysregulation. Regranion has recently acquired a potent novel small molecule HSP90 inhibitor (RGRN-305, previously Debio0932) with a good safety profile and attractive pharmacological properties that shows alleviation of psoriatic symptoms, reduced epidermal thickness, and dramatic reduction in levels of TNFα and IL-17, pro-inflammatory cytokines in clinically relevant animal models of psoriasis. These studies laid the foundation for ongoing clinical evaluation in the treatment of moderate-to- severe psoriasis (ClinicalTrials.gov Identifier: NCT03675542) and set a precedence for investigation of HSP90 as a therapeutic target in AD. The focus of this proposal is to accomplish key milestones that will transition this technology for commercialization as a safe and efficacious oral AD therapeutic that targets the upstream proteomic mediators of the disease. The study aims involve i.) rigorous evaluation of the efficacy and mechanism of action of oral RGRN-305 in multiple clinically relevant AD models that incorporate a comparative efficacy study versus corticosteroid treatment, and ii.) characterization of the gene and protein expressions of HSP90 pathway- related markers in normal, nonlesional and AD lesional human skin samples from moderate-to-severe AD patients. A role for HSP90 in the pathogenesis and persistence of AD has not been elucidated. Given that the etiology of AD is multifaceted, characterizing the expression profile of epidermal HSP90 pathway and related cytokines and chemokines will permit insight into the therapeutic potential and opportunity for individualized therapy with RGRN-305.