title: The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia.
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 linesin vitroUsing 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.
authors: KU Leuven Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
authors: Thomas
authors: T
authors: Vercruysse
authors: KU Leuven Department of Human Genetics, Laboratory of Molecular Biology of Leukemia, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
authors: Jolien
authors: J
authors: De Bie
authors: KU Leuven Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
authors: Jasper E
authors: JE
authors: Neggers
authors: KU Leuven Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
authors: Maarten
authors: M
authors: Jacquemyn
authors: KU Leuven Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
authors: Els
authors: E
authors: Vanstreels
authors: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
authors: Jonathan L
authors: JL
authors: Schmid-Burgk
authors: Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
authors: Veit
authors: V
authors: Hornung
authors: Karyopharm Therapeutics Inc., Newton, Massachusetts.
authors: Erkan
authors: E
authors: Baloglu
authors: Karyopharm Therapeutics Inc., Newton, Massachusetts.
authors: Yosef
authors: Y
authors: Landesman
authors: Karyopharm Therapeutics Inc., Newton, Massachusetts.
authors: William
authors: W
authors: Senapedis
authors: Karyopharm Therapeutics Inc., Newton, Massachusetts.
authors: Sharon
authors: S
authors: Shacham
authors: KU Leuven Department of Human Genetics, Laboratory of Molecular Biology of Leukemia, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
authors: Antonis
authors: A
authors: Dagklis
authors: KU Leuven Department of Human Genetics, Laboratory of Molecular Biology of Leukemia, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
authors: Jan
authors: J
authors: Cools
authors: KU Leuven Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium. dirk.daelemans@kuleuven.be.
authors: Dirk
authors: D
authors: Daelemans
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D000072669:Gene Editing; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics; D013844:Thiazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000970:Antineoplastic Agents; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D000097606:Exportin 1 Protein