FR-027 (FR027) is a potent, reversible Exportin 1 (XPO1, CRM1) inhibitor, covalently modifies XPO1 Cys528, inhibits XPO1-NES (nuclear export signal) binding, inhibits XPO1-mediated nuclear export of the SV40NLS-AcGFP-PKINES reporter with IC50 of 54 nM.
targets Cys528 through nucleophilic aromatic substitution.
FR-027 represents a mechan istically distinct class of covalent XPO1 inhibitors that inhibit nuclear export by covalently modifying Cys528 while maintaining the NES binding groove in a closed configuration, thereby preventing ASB8 recruitment and subsequent XPO1 degradation.
FR-027 inhibits XPO1 in a reversible manner.
FR-027 inhibits XPO1-mediated nuclear export with efficacy comparable to selinexor or eltanexor.
FR-027 (2.5 uM) induced pronounced nuclear accumulation of RanBP1 in wild-type Jurkat cells, does not alter the subcellular localization of RanBP1 in XPO1C528S mutant cells.
FR-027 induces potent and XPO1-dependent cytotoxicity acrossa broad panel of tumor cell lines.
FR-027 is orally bioavailable and demonstrates excellent blood brain barrier penetration.
FR-027 (100 mg/kg) significantly delayed tumor growth in orthotopicmurinebraintumormodel by intracranial injection of U87-MG-Luc2 cells into BALB/c nude mice, does not affect platelet, neutrophil, or lymphocyte counts.