STAT Inhibitors for Asthma Therapy

哮喘是一种影响所有年龄段的成人和儿童的慢性肺部疾病，在过去的几十年里，哮喘的发病率、患病率和严重程度都显著增加，在美国的患病率为8.4%。目前的哮喘治疗标准包括长效β 2肾上腺素能受体激动剂（缓解气道收缩）和糖皮质激素（减少气道炎症）的联合治疗。虽然这种治疗最初是有效的，但对治疗的耐药性以及与哮喘相关的过高死亡率和与糖皮质激素相关的其他严重不良反应仍然是严重的和持续存在的问题，值得改进的方法。哮喘患者气道中IL-4和IL-13细胞因子水平升高，导致粘液产生、气道对乙酰胆碱（AHR）的高反应性、嗜酸性粒细胞募集、辅助性T细胞2 （TH2）激活、免疫球蛋白类转化为IgE和炎症。这两种细胞因子通过IL-4Ralpha发出信号并激活JAK1、JAK3或Tyk2，从而导致信号转换器和转录激活因子6 （STAT6）的磷酸化。然后pSTAT6通过SH2结构域- ptyr641相互作用进行二聚化，易位到细胞核，参与导致哮喘的基因表达。重要的是，哮喘患者支气管上皮中的pSTAT6水平升高，STAT6敲除小鼠不会发生AHR或与哮喘相关的肺部病理。综上所述，这些研究支持了抑制STAT6活性是治疗哮喘的一种潜在方式的假设。Atrapos， LLC是一家私人控股的临床前阶段治疗公司，致力于哮喘创新疗法的进步。Atropos的创新是由Atropos联合创始人dr。约翰·麦克默里和大卫·科里。我们的先导分子PM-43I是一种小分子、细胞渗透性、磷酸酶稳定的磷酸肽模拟物，靶向STAT6的SH2结构域，阻止il - 4rα的募集和随后导致哮喘表型的转录活性。我们的体内实验表明，PM-43I可以防止真菌诱导的哮喘，更重要的是，可以逆转哮喘的许多标志性特征，包括气道收缩、肺部炎症和肺粘液产生。该提案的重点是完成关键里程碑，通过测量该分子从肺部的吸收、分布到其他组织、代谢和消除以及潜在毒性，进一步将该技术转化为哮喘市场的商业化。该项目被组织成两个可测量的具体目标：1。表征PM-43I和PM-43I的药代动力学特征。评估PM-43I的潜在毒性。

Asthma, a chronic disease of the lungs that affects adults and children of all ages, has markedly increased in incidence, prevalence and severity over the past several decades with a prevalence of 8.4% in the U.S. The current standard of care for asthma consists of the combination of long acting beta2 adrenergic receptor agonists, which relieve airway constriction, and glucocorticosteroids, which reduce airway inflammation. While this treatment is initially effective, resistance to therapy as well as excess asthma-related mortality and other serious adverse effects related to glucocorticosteroids remain serious and ongoing problems deserving of improved approaches. Asthma patients have elevated levels of the cytokines IL-4 and IL-13 in their airways, which result in mucus production, airway hyperresponsiveness to acetylcholine (AHR), eosinophil recruitment, helper T cell 2 (TH2) activation, immunoglobulin class switching to IgE, and inflammation. These two cytokines signal through IL-4Ralpha and activate JAK1, JAK3, or Tyk2 which leads to phosphorylation of the signal transducer and activator of transcription 6 (STAT6). pSTAT6 then dimerizes via reciprocal SH2 domain-pTyr641 interactions, translocates to the nucleus, and participates in the expression of genes leading to asthma. Importantly, pSTAT6 levels are elevated in the bronchial epithelium of asthma patients and STAT6 knockout mice do not develop AHR or lung pathology associated with asthma. Taken together, these studies support the hypothesis that inhibiting the activity of STAT6 is a potential modality for asthma treatment. Atrapos, LLC is a privately-held preclinical stage therapeutics company dedicated to the advancement of innovative therapies for asthma. Atropos’ innovation is the direct result of basic research conducted by Atropos co-founders Drs. John McMurray and David Corry. Our lead molecule, PM-43I, is a small-molecule, cell-permeable, and phosphatase-stable phosphopeptide mimetic that targets the SH2 domain of STAT6 and prevents recruitment to IL-4Ralpha and the subsequent transcriptional activity leading to the asthma phenotype. Our in vivo experiments demonstrate that PM-43I prevents the induction of fungal-induced asthma and, more importantly, reverses many of the hallmark features of asthma including airway constriction, lung inflammation, and lung mucus production. The focus of this proposal is to accomplish key milestones that will further transition this technology for commercialization for the asthma market by measuring absorption from the lung, distribution to other tissues, metabolism and elimination and potential toxicity of the molecule. The project is organized into two measureable Specific Aims: 1. Characterize the pharmacokinetic profile of PM-43I and 2. Assess potential toxicities of PM-43I.