Principal Investigator:
Timothy Hla
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
Resources
Intellectual Property
Patents
- US Patent Application: US20200407339A1. "Pyridinone- and pyridazinone-based compounds and uses thereof." Published Dec 31, 2020.
- EP Patent Application: EP3762377A1. "Pyridinone- and pyridazinone-based compounds and medical uses thereof." Published Jan 13, 2021.
Cornell Reference
- 8089
Contact Information
For additional information please contact
Jeffrey James
Associate Director, Business Development and Licensing
Phone: (646) 962-4194
Email: jaj268@cornell.edu