Thursday, April 25, 2024
4/25/2024
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.
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