Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Hematology, ANTICANCER ACTIVITY, DRUG-RESISTANCE, CELL-SURVIVAL, CRM1, EXPRESSION, PROTEIN, APOPTOSIS, RITUXIMAB, TRANSPORT, MECHANISM, Acrylates, Active Transport, Cell Nucleus, Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, Cells, Cultured, Crystallography, X-Ray, Humans, Immunoblotting, Interleukin-10, Interleukin-6, Karyopherins, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, Mice, SCID, Mice, Transgenic, Microscopy, Confocal, Models, Molecular, Molecular Structure, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins, RNA Interference, Receptors, Cytoplasmic and Nuclear, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Triazoles, Exportin 1 Protein, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Immunology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3213 Paediatrics

Abstract:

The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies.