The second-generation exportin-1 inhibitor KPT-8602 demonstrates potent activity against acute lymphoblastic leukemia

Vercruysse, Thomas; De Bie, Jolien; Neggers, Jasper; Jacquemyn, Maarten; Vanstreels, Els; Schmid-Burgk, Jonathan Leo; Hornung, Veit; Baloglu, Erkan; Landesman, Yosef; Senapedis, William; Shacham, Sharon; Dagklis, Antonis; Cools, Jan; Daelemans, Dirk

doi:10.1158/1078-0432.CCR-16-1580

The second-generation exportin-1 inhibitor KPT-8602 demonstrates potent activity against acute lymphoblastic leukemia

Author:

Vercruysse, Thomas

De Bie, Jolien ; Neggers, Jasper ; Jacquemyn, Maarten ; Vanstreels, Els ; Schmid-Burgk, Jonathan Leo ; Hornung, Veit ; Baloglu, Erkan ; Landesman, Yosef ; Senapedis, William ; Shacham, Sharon ; Dagklis, Antonis ; Cools, Jan ; Daelemans, Dirk

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, CHRONIC LYMPHOCYTIC-LEUKEMIA, NUCLEAR EXPORT, SELECTIVE INHIBITOR, CRM1, EXPRESSION, CANCER, PROGNOSIS, MECHANISM, CRM1/XPO1, PROTEIN, Active Transport, Cell Nucleus, Animals, Antineoplastic Agents, Apoptosis, CRISPR-Cas Systems, Cell Line, Tumor, Gene Editing, Humans, Karyopherins, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Cytoplasmic and Nuclear, Thiazoles, Xenograft Model Antitumor Assays, Exportin 1 Protein, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

Abstract:

Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports many cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibition of 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 - 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).