CRM1 Inhibitor IV, KPT-251

A cell-permeable, irreversible, triazole-containing heterotricyclic CRM1 inhibitor that effectively blocks CRM1-mediated nuclear export (complete HIV-1 Rev nuclear retention after 4 h 1µM incubation in RevGFP-expressing U2OS cells) via covalent interaction with Cys528 (numbering based on human sequence) in the CRM1 NES- (nuclear export signal) binding groove, while being ineffective against CRM1^C528S-Rev interaction in RevBFP-expressing HeLa cells. Exhibits antileukemic activity in primary human CD19⁺ CLL (chronic lymphocytic leukemia) cultures (IC₅₀<500 nM) via apoptosis induction even in the presence of stroma cells or other known CLL survival stimuli, while exhibiting little cytotoxicity toward CD56⁺ NK cells from healthy donors (1 µM; up to 72 h). KPT-251 is orally available in mice (t_max = 0.5 h; t_1/2 = 3.83 h; C_max = 439 ng/mL; AUC_INF = 1590 h·ng/mL; 10 mg/kg p.o.) and reported to prolong the survival of SCID mice (75 mg/kg p.o.) engrafted with murine Eμ-TCL1 (mean survival time = 130.5 d vs. 72 d, respectively, with or without treatment) and human MV4-11 leukemia (62% survival rate on d 60 vs. 24% on d 34, respectively, with or without treatment) in vivo.

Cell permeable: yes

Primary Target
XPO1

Reversible: no

Packaged under inert gas

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

Etchin, J., et al. 2013. Leukemia.27, 66.
Lapalombella, R., et al. 2012. Blood.120, 4621.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)