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

体内 药理学 化学 白血病 癌症研究 内科学 生物 医学 遗传学
作者
Thomas Vercruysse,Jolien De Bie,Jasper E. Neggers,Maarten Jacquemyn,Els Vanstreels,Jonathan L. Schmid-Burgk,Veit Hornung,Erkan Baloglu,Yosef Landesman,William Senapedis,Sharon Shacham,Antonis Dagklis,Jan Cools,Dirk Daelemans
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:23 (10): 2528-2541 被引量:54
标识
DOI:10.1158/1078-0432.ccr-16-1580
摘要

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.
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