The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia

• Published in: Clinical cancer research Vol. 23; no. 10; pp. 2528 - 2541
• Main Authors: Vercruysse, Thomas, De Bie, Jolien, Neggers, Jasper E, Jacquemyn, Maarten, Vanstreels, Els, Schmid-Burgk, Jonathan L, Hornung, Veit, Baloglu, Erkan, Landesman, Yosef, Senapedis, William, Shacham, Sharon, Dagklis, Antonis, Cools, Jan, Daelemans, Dirk
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.05.2017
• Subjects: Active Transport, Cell Nucleus - drug effects; Acute lymphoblastic leukemia; Animal models; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antitumor activity; Apoptosis; Apoptosis - drug effects; Biotechnology; Cancer; Cargo; Caspase; Cell death; Cell Line, Tumor; Clinical trials; CRISPR; CRISPR-Cas Systems; Experimental design; Exportin 1 Protein; Gene Editing; Genomes; Hematopoiesis; Humans; Inhibition; Inhibitors; Karyopherins - antagonists & inhibitors; Karyopherins - genetics; Leukemia; Lymphatic leukemia; Medical research; Mice; Nuclear transport; Pharmacology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein transport; Proteins; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Thiazoles - administration & dosage; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-16-1580

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). 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. , anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models. KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines 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. , 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. 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. .