XPO1-Targeting Selective Inhibitors of Transcriptional Activation Suppress Graft-versus-Host Disease

Area of Science:

• Molecular Biology
• Immunology
• Drug Discovery

Background:

• Exportin-1 (XPO1) facilitates nuclear-to-cytoplasmic protein transport.
• Selective inhibitors of nuclear export (SINEs) like Selinexor are approved for hematological cancers.
• A novel class of XPO1 modulators, SITAs, suppress T cell activation without affecting nuclear export or cell viability.

Purpose of the Study:

• Analyze structure-activity relationships of two distinct SITA subseries.
• Evaluate the therapeutic potential of optimized XPO1-targeting SITAs.
• Explore XPO1 as a target for T cell-driven diseases beyond oncology.

Main Methods:

• Structure-activity relationship analysis of pyridine- and pyrrolotriazine-containing SITAs.
• In vitro cellular potency assays (EC50).
• In vivo XPO1 engagement and efficacy studies in a mouse model of graft versus host disease.

Main Results:

• Pyridine-containing SITAs achieved high cellular potency (1 nM EC50).
• Pyrrolotriazine-containing SITAs balanced potency with favorable physicochemical properties.
• Lead SITA molecules demonstrated in vivo XPO1 engagement, efficacy in GVHD models, and superior tolerability compared to Selinexor.

Conclusions:

• Optimized XPO1-targeting SITAs represent a promising therapeutic strategy.
• XPO1 is a viable therapeutic target for T cell-driven diseases.
• SITAs offer potential for treating conditions beyond current oncology indications.