Inhibition of the Rho/MRTF/SRF Pathway as a New Treatment for Systemic Sclerosis

抑制 Rho/MRTF/SRF 通路作为系统性硬化症的新治疗方法

• 批准号: 8671854
• 负责人: Scott D Larsen
• 金额: $ 65.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671854
• 关键词: Actins; Address; Adverse effects; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Binding; Bleomycin; Cell Nucleus; Cessation of life; Chemicals; Collagen; Connective Tissue Diseases; Cyclophosphamide; Dermal; Development; Diagnosis; Disease; Drug Kinetics; Etiology; Extracellular Matrix; F-Actin; Fibroblasts; Fibrosis; G Actin; Gastrointestinal tract structure; Genes; Genetic Transcription; Health; Heart; Human; Immune system; Immunosuppressive Agents; Inflammatory; Kidney; Lead; Liver Microsomes; Luciferases; Lung; Maximum Tolerated Dose; Mediating; Medical; Metabolic; Metabolism; Methotrexate; Modeling; Mus; Myofibroblast; Organ; Outcome; Pathology; Pathway interactions; Patients; Permeability; Positioning Attribute; Prevention; Process; Production; Property; Research; Scleroderma; Series; Serum Response Element; Serum Response Factor; Signal Pathway; Site; Skin; Smooth Muscle Actin Staining Method; Solubility; Stimulus; Systemic Scleroderma; Testing; Tissues; Up-Regulation; Vascular System; Work; Wound Healing; analog; aqueous; cytotoxic; design; effective therapy; extracellular; improved; in vitro Assay; in vitro activity; in vivo; in vivo Model; inhibitor/antagonist; innovation; lipophilicity; mouse model; myocardin; novel; novel therapeutic intervention; physical property; prevent; promoter; rho; small molecule; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Systemic sclerosis (scleroderma, SSc) is a devastating fibrotic disease of the connective tissues, for which there are no satisfactory treatment options. It is a multisystem disorder that can cause fibrosis of the skin and internal organs, including lungs, heart, kidneys and the gastrointestinal tract. SSc afflicts 100,000-150,000 people in the US alone, with approximately 1500 new cases diagnosed each year. Current management of SSc entails the use of immunosuppressives such as methotrexate and cyclophosphamide, which are cytotoxic and of limited efficacy. Although the pathology and progression of SSc have been well described, the etiology of the disease is still not clear. The hallmark of SSc and other fibroses is the transition of normal fibroblasts into myofibroblasts, which are characterized by expression of alpha- smooth muscle actin (α-SMA) and production of collagen-rich extracellular matrix (ECM). This pro-fibrotic fibroblast-to-myofibroblast transitin can be induced by a number of extracellular stimuli, most of which appear to depend on the RhoA signaling pathway. This pathway leads to the release of G-actin-bound myocardin- related transcription factor (MRTF), subsequent accumulation of MRTF in the nucleus, binding of MRTF to serum response factor (SRF) on the serum response element (SRE) promoter, and consequent upregulation of expression of a number of pro-fibrotic genes, including ACTA2, the gene encoding for α-SMA. We have discovered and developed a novel class of small molecule inhibitors of the Rho/MRTF/SRF gene transcription pathway. A lead compound from this series (CCG-203971) inhibits expression of α-SMA in both TGF-β-stimulated normal dermal fibroblasts as well as skin myofibroblasts from SSc patients. Despite this promising in vitro activity, CCG-203971 has modest potency and poor pharmacokinetic (PK) properties that limit its use as a probe for studying the effects of inhibiting the Rho/MRTF/SRF pathway in in vivo models of fibrosis. The overarching hypothesis of this proposal is that pharmacological inhibition of Rho/MRTF/SRF-mediated gene transcription will be an effective new treatment strategy for SSc. Our approach will be to: 1) optimize the lead CCG-203971 for both potency and physicochemical properties predictive of good PK; 2) evaluate the best new analogs for in vivo PK; and 3) evaluate optimal probes for efficacy in two complementary mouse models of fibrosis. This proposal is innovative in that it will attempt to treat or prevent fibrosis through disruptionof the Rho/MRTF/SRF signaling pathway at a point that is downstream of and common to multiple extracellular pro-fibrotic stimuli. This work is significant in that it will attempt for the first ime to directly prevent the fundamental myofibrblast differentiation that underlies fibrosis. Finally, the ultimate impact of this work will be progress toward the development of an entirely new therapy for SSc and potentially many other fibrotic diseases.

描述（由申请方提供）：系统性硬化症（硬皮病，SSc）是一种破坏性结缔组织纤维化疾病，目前尚无令人满意的治疗方案。它是一种多系统疾病，可导致皮肤和内脏器官纤维化，包括肺、心脏、肾脏和胃肠道。仅在美国就有10万至15万人患有SSc，每年诊断出约1500例新病例。目前SSc的治疗需要使用免疫抑制剂，如甲氨蝶呤和环磷酰胺，它们具有细胞毒性且疗效有限。虽然SSc的病理和进展已得到很好的描述，但该病的病因仍不清楚。SSc和其他纤维化的标志是正常成纤维细胞转变为肌成纤维细胞，其特征在于表达α-平滑肌肌动蛋白（α-SMA）和产生富含胶原蛋白的细胞外基质（ECM）。这种促纤维化成纤维细胞到肌成纤维细胞的过渡蛋白可以由许多细胞外刺激诱导，其中大部分似乎依赖于RhoA信号通路。该途径导致G-肌动蛋白结合的心肌蛋白相关转录因子（MRTF）释放，随后MRTF在细胞核中蓄积，MRTF与血清反应元件（SRE）启动子上的血清反应因子（SRF）结合，随后上调许多促纤维化基因（包括编码α-SMA的基因ACTA 2）的表达。我们已经发现并开发了一类新的Rho/MRTF/SRF基因转录途径的小分子抑制剂。该系列的先导化合物（CCG-203971）可抑制TGF-β刺激的正常真皮成纤维细胞以及SSc患者皮肤肌成纤维细胞中α-SMA的表达。尽管有这种有希望的体外活性，CCG-203971具有适度的效力和较差的药代动力学（PK）特性，这限制了其作为探针用于研究在体内纤维化模型中抑制Rho/MRTF/SRF途径的作用。该建议的总体假设是，Rho/MRTF/SRF介导的基因转录的药理学抑制将是SSc的有效新治疗策略。我们的方针是：1）优化先导CCG-203971的效力和预测良好PK的物理化学性质; 2）评估用于体内PK的最佳新类似物;和3）评估用于两种互补的纤维化小鼠模型中的功效的最佳探针。该提议是创新的，因为它将尝试通过在多个细胞外促纤维化刺激的下游和共同点处破坏Rho/MRTF/SRF信号传导途径来治疗或预防纤维化。这项工作的重要性在于，它将首次尝试直接阻止纤维化的基础肌母细胞分化。最后，这项工作的最终影响将是朝着SSc和潜在的许多其他纤维化疾病的全新疗法的发展取得进展。