Developing a Novel E3 Ligase based Anti-inflammatory for ARDS

急性呼吸窘迫综合征（ARDS）是一种毁灭性的炎症性疾病 由败血症或严重肺炎如SARS-Cov-2引起。一种特异性的特征， ARDS是继发于宿主细胞细胞因子大量释放的严重组织损伤。激活 肿瘤坏死因子受体相关因子（TRAF）和炎性小体蛋白的表达是 这些蛋白质将细胞表面信号与细胞因子释放联系起来，因此对炎症至关重要。的 该建议的机制平台在于我们发现了一种相对较新的蛋白质， Fbxo 3是一种泛素E3连接酶亚基，其有效地刺激人细胞因子分泌。 通过激活TRAF和炎性小体来刺激炎性细胞。我们以前设计和 将Fbxo 3抑制剂BC-1261推进到开放IND，然而，由于 临床前观察到癫痫发作，限制了临床给药，从而最大限度地减少了 在人类中实现有效暴露的可能性。认识到建立 在BC-1261取得成就的基础上，本申请中概述的研究策略是 设计了具体的里程碑，以解决BC-1261的关键缺陷。这里我们 提出药物化学和铅优化，以开发和提供一个强大的小- 分子Fbxo 3靶向的开发候选物，具有改善的治疗指数， 癫痫发作潜力（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， IND赋能研究的候选人（目标2）。此外，候选人将证明剂量- 在三种可翻译的ARDS实验模型中，包括SARS- 具有PK特性的Cov-2仓鼠模型支持基于医院的重症监护治疗 以抑制急性肺损伤患者的免疫功能失调。成功 该计划的完成将带来一个变革，一流的口服E3连接酶 重症药物治疗

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.