5.00505

CRM1 Inhibitor IV, KPT-251

• Synonym(s): CRM1 Inhibitor IV, KPT-251, KPT251, (Z)-2-(2-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)vinyl)-1,3,4-oxadiazole, Exportin 1 Inhibitor IV, Chromosome Region Maintenance 1 Protein Inhibitor IV, CRM1 Inhibitor IV, XPO1 Inhibitor IV
• Empirical Formula (Hill Notation): C₁₄H₇F₆N₅O
• Molecular Weight: 375.23

Properties

• Assay: ≥99% (HPLC)
• Quality Level: 100
• form: solid
• manufacturer/tradename: Calbiochem^®
• storage condition: OK to freeze; protect from light
• color: white
• solubility: DMSO: 25 mg/mL
• storage temp.: −20°C

Description

General description

A cell-permeable, irreversible, triazole-containing heterotricyclic CRM1 inhibitor that effectively blocks CRM1-mediated nuclear export (4 h 1µM in U2OS cells) via covalent interaction with CRM1 NES- (nuclear export signal) binding groove cysteine (Cys528 in human). Exhibits antileukemic activity against primary human CD19⁺ CLL (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). Reported to prolong the survival of SCID mice (75 mg/kg p.o.) engrafted with murine Eμ-TCL1 or human MV4-11 leukemia in vivo.

Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water.

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.

Biochem/physiol Actions

Cell permeable: yes

Primary Target
XPO1

Reversible: no

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

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

Other Notes

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

Legal Information

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

Safety Information

• Storage Class Code: 11 - Combustible Solids
• WGK: WGK 3
• Flash Point(F): Not applicable
• Flash Point(C): Not applicable