Related Experiment Video
Updated: Mar 13, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia
Thomas Vercruysse1, Jolien De Bie2,3, Jasper E Neggers1
1KU Leuven Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
Abstract:
Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug-target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL).Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602's drug-target interaction. In vivo, anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models.Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo, KPT-8602 showed potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis.Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528-41. ©2016 AACR.
Insights
The novel drug KPT-8602 effectively targets exportin-1 (XPO1) to induce cancer cell death. This second-generation Selective Inhibitor of Nuclear Export (SINE) compound shows potent anti-leukemia activity in models of acute lymphoblastic leukemia (ALL).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Exportin-1 (XPO1) is crucial for nuclear export of cargo proteins; its inhibition can induce cancer cell death.
- First-generation Selective Inhibitors of Nuclear Export (SINE) compounds like selinexor (KPT-330) show clinical activity in cancer.
- Second-generation SINE compound KPT-8602 offers improved tolerability and daily dosing potential.
Purpose of the Study:
- To investigate and validate the drug-target interaction of KPT-8602 with XPO1.
- To explore the anti-leukemic activity of KPT-8602 against acute lymphoblastic leukemia (ALL).
Main Methods:
- Assessed KPT-8602's effect on XPO1 function and XPO1-cargo interactions in leukemia cell lines.
- Utilized CRISPR/Cas9 genome editing to create mutant XPO1 leukemia cells for drug-target validation.
- Evaluated anti-ALL activity in mouse models and patient-derived xenografts.
Main Results:
- KPT-8602 induced caspase-dependent apoptosis in various leukemic cell lines.
- Specificity for XPO1 cysteine 528 was confirmed, validating the drug-target interaction.
- KPT-8602 demonstrated potent anti-leukemia activity in vivo without impacting normal hematopoiesis.
Conclusions:
- KPT-8602 exhibits high specificity for XPO1 inhibition.
- The compound shows significant anti-leukemic potential, supporting its clinical use for ALL.
- KPT-8602 represents a promising therapeutic strategy for acute lymphoblastic leukemia.
