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

Exportin-1 (XPO1) is a mediator of nuclear-to-cytoplasmic protein trafficking. The XPO1-targeting selective inhibitor of nuclear export (SINE) Selinexor is FDA-approved for relapsed hematological malignancies. Recently, we reported a unique class of XPO1 modulators that suppressed T cell activation without impairing nuclear export or cell viability (the selective inhibitors of transcriptional activation, or SITAs), suggesting that XPO1 may be a therapeutic target in T cell-driven diseases. Here, we analyzed structure-activity relationships of two structurally distinct subseries of SITAs. A set of pyridine-containing structures attained high cellular potencies (EC 1 nM), while a complementary set of pyrrolotriazine-containing molecules balanced cellular potency with desirable physicochemical properties. Lead molecules from both subseries demonstrated in vivo XPO1 engagement, were efficacious in a mouse model of graft versus host disease, and showed superior tolerability to Selinexor. This study provides evidence that optimized XPO1-targeting SITAs can extend XPO1 as a therapeutic target to indications beyond oncology.