Irreversible S1PR2 Antagonists for the Treatment of Inflammation and Fibrosis

Background & Unmet Need

• Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates many physiological (and pathophysiological) processes
• The S1PR2 receptor is an abundant GPCR widely expressed in the endothelium, in addition to fibrogenic and immune cells, and is upregulated by inflammation
• S1PR2 modulates several metabolic pathways in the liver, including regeneration after hepatic injury
• S1PR2 is believed to be one of the key drivers of tissue injury and fibrosis, and is thus a promising therapeutic target
• Unmet Need: Novel anti-fibrotic agents that prevent disease progression by targeting pro-fibrotic factors such as S1PR2

Technology Overview

• The Technology: Lead compounds with demonstrated efficacy in the mouse bile duct ligation model
• Irreversible S1PR2 antagonists TDI-6142 and TDI-6408 were developed based on CYM-5520 following extensive SAR studies
• TDI-6408 is a functional S1PR2 antagonist that binds irreversibly, leading to receptor endocytosis and thus overcomes the challenge of outcompeting the high concentration of circulating S1P ligand
• PoC Data: TDI-6408 dramatically increased survival (73% of animals) compared to vehicle control (27%) in the mouse bile duct ligation model
• TDI-6408 did not exhibit useful activity in the carbon tetrachloride (CCl4) fibrosis model, suggesting additional fibrosis models should be explored
• Safety: No significant interactions in broad screen of receptors, enzymes, hormones, and ion channels

Technology Applications

• Prevention of fibrotic disease in the lung and liver
• Treatment of highly angiogenic tumors (e.g., glioblastoma, renal cell carcinoma)
• Treatment of age-related macular degeneration (AMD)
• Treatment of cytokine release syndrome (CRS) associated with CAR-T therapy

Technology Advantages

• Irreversible antagonist, resulting in S1PR2 internalization and degradation
• Demonstrated efficacy in mouse bile duct ligation model
• No significant interactions in a broad array of receptor, enzyme, hormone, and ion channel screens