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 (EC50 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.