title: Identification of nuclear export inhibitors with potent anticancer activity in vivo.
abstract: The export protein CRM1 is required for the nuclear export of a wide variety of cancer-related "cargo" proteins including p53, c-Abl, and FOXO-3A. Leptomycin B (LMB) is a highly specific inhibitor of CRM1 with significant in vitro potency but limited in vivo efficacy due to toxicity. We now report a series of semisynthetic LMB derivatives showing substantially improved therapeutic windows. Exposure of cancer cells to these compounds leads to a rapid and prolonged block of nuclear export and apoptosis. In contrast to what is observed in cancer cells, these agents induce cell cycle arrest, but not apoptosis, in normal lung fibroblasts. These new nuclear export inhibitors (NEI) maintain the high potency of LMB, are up to 16-fold better tolerated than LMB in vivo, and show significant efficacy in multiple mouse xenograft models. These NEIs show the potential of CRM1 inhibitors as novel and potent anticancer agents.
authors.affiliation: Kosan Biosciences, Inc, Hayward, California 92121, USA. sarah.mutka@n30pharma.com
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mutka
authors.forename: Wen Qing
authors.initials: WQ
authors.lastname: Yang
authors.forename: Steven D
authors.initials: SD
authors.lastname: Dong
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Ward
authors.forename: Darren A
authors.initials: DA
authors.lastname: Craig
authors.forename: Pieter B M W M
authors.initials: PB
authors.lastname: Timmermans
authors.forename: Sumati
authors.initials: S
authors.lastname: Murli
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D008168:Lung / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000903:Antibiotics, Antineoplastic; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C495901:TP53 protein, human; C038753:leptomycin B