Developing a Novel E3 Ligase based Anti-inflammatory for ARDS

急性呼吸窘迫综合征(ARDS)是一种破坏性的促炎性疾病 由败血症或严重肺炎引起，如SARS-CoV-2。的一种病象特征 ARDS是一种严重的组织损伤，继发于宿主细胞细胞因子的大量释放。激活 肿瘤坏死因子受体相关因子(TRAF)和炎症体蛋白 对炎症至关重要，因为这些蛋白质将细胞表面信号与细胞因子释放联系起来。这个 这一提议的机械平台在于我们发现了一种相对较新的蛋白质， Fbxo3，一种泛素E3连接酶亚单位，能有效刺激人类分泌细胞因子 通过激活TRAF和炎性小体来激活炎症细胞。我们之前设计了和 将Fbxo3抑制剂BC-1261提高到开放的Ind，然而，由于 癫痫发作是在临床前观察到的，限制了临床上的剂量，从而最大限度地减少了 在人体内实现有效暴露的可能性。认识到建设的机会 在BC-1261的基础上，本申请中概述的研究策略是 设计了特定的里程碑，以解决BC-1261的关键缺陷。在这里，我们 提出药物化学并引领优化，以开发和交付强大的小型- Fbxo3分子靶向开发候选药物，治疗指数提高 对癫痫潜伏期的疗效(目标1)。我们还将执行药效学和 先导化合物的药代动力学(PK)研究以推荐合适的开发 促进可持续发展研究的候选人(目标2)。此外，候选人将展示剂量- 包括SARS在内的三种可翻译ARDS实验模型对口腔活动的依赖性 CoV-2仓鼠模型，具有PK属性，支持以医院为基础的危重治疗 抑制急性肺损伤患者功能紊乱的免疫反应。成功 该项目的完成将带来一种变革性的、一流的口腔E3连接酶 危重疾病的药物疗法。

Acute respiratory distress syndrome (ARDS) is a devastating, proinflammatory disorder resulting from sepsis or severe pneumonia such as SARS-Cov-2. A pathognomonic feature of ARDS is severe tissue injury secondary to a profound release of host cell cytokines. Activation of tumor necrosis factor receptor associated factor (TRAF) and the inflammasome proteins are crucial to inflammation as these proteins link cell surface signals to cytokine release. The mechanistic platform of this proposal resides on our discovery of a relatively new protein, Fbxo3, a ubiquitin E3 ligase subunit, that potently stimulates cytokine secretion from human inflammatory cells by activating TRAFs and inflammasomes. We previously designed and advanced an Fbxo3 inhibitor, BC-1261, to an open IND, however, development was halted as seizures were observed preclinically, limiting dosing in the clinic and thereby minimizing the likelihood of achieving efficacious exposures in humans. Recognizing the opportunity to build upon the achievements of BC-1261, the research strategy outlined in this application is designed with specific milestones to address the critical shortcomings of BC-1261. Here, we propose medicinal chemistry and lead optimization to develop and deliver a potent small- molecule Fbxo3-targeted development candidate with an improved therapeutic index of efficacy to seizure potential (Aim 1). We will also execute pharmacodynamics and pharmacokinetic (PK) studies of lead compounds to nominate a suitable development candidate for IND-enabling studies (Aim 2). Additionally, the candidate will demonstrate dose- dependent oral activity in three translatable ARDS experimental models including a SARS- Cov-2 hamster model with PK properties that support a hospital-based, critical-care therapeutic to inhibit the dysfunctional immune response in acute lung injury patients. Successful completion of this program will bring forth a transformative, first-in-class oral E3 ligase pharmacotherapeutic for critical illness.