Irreversible S1PR2 Antagonists for the Treatment of Inflammation and Fibrosis

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

Data chart: A high dose of TDI-6408 conferred a significant survival benefit (73%) in bile duct ligated mice compared to low dose TDI6408 (33%) and vehicle control (27%).

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

Dr. Jeff James

For additional information please contact

Jeffrey James
Associate Director, Business Development and Licensing
Phone: (646) 962-4194
Email: jaj268@cornell.edu