title: Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic.
abstract: Karyopherin beta 1 (Kpnβ1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnβ1 expression was found in certain cancers and Kpnβ1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnβ1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnβ1 and Inhibitor of Nuclear Import-43, INI-43 (3-(1H-benzimidazol-2-yl)-1-(3-dimethylaminopropyl)pyrrolo[5,4-b]quinoxalin-2-amine) was investigated further as it interfered with the nuclear localization of Kpnβ1 and known Kpnβ1 cargoes NFAT, NFκB, AP-1, and NFY and inhibited the proliferation of cancer cells of different tissue origins. Minimum effect on the proliferation of noncancer cells was observed at the concentration of INI-43 that showed a significant cytotoxic effect on various cervical and esophageal cancer cell lines. A rescue experiment confirmed that INI-43 exerted its cell killing effects, in part, by targeting Kpnβ1. INI-43 treatment elicited a G2-M cell-cycle arrest in cancer cells and induced the intrinsic apoptotic pathway. Intraperitoneal administration of INI-43 significantly inhibited the growth of subcutaneously xenografted esophageal and cervical tumor cells. We propose that Kpnβ1 inhibitors could have therapeutic potential for the treatment of cancer. Mol Cancer Ther; 15(4); 560-73. ©2016 AACR.
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: van der Watt
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Alicia
authors.initials: A
authors.lastname: Chi
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Tamara
authors.initials: T
authors.lastname: Stelma
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Catherine
authors.initials: C
authors.lastname: Stowell
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Erin
authors.initials: E
authors.lastname: Strydom
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Sarah
authors.initials: S
authors.lastname: Carden
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Angus
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Kate
authors.initials: K
authors.lastname: Hadley
authors.affiliation: Confocal and Light Microscope Imaging Facility, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lang
authors.affiliation: Center for Cancer Research, The Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Center for Cancer Research, The Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.affiliation: Department of Medicine, J.G. Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.affiliation: Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. Virna.Leaner@uct.ac.za.
authors.forename: Virna D
authors.initials: VD
authors.lastname: Leaner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D039301:Computers, Molecular; D004195:Disease Models, Animal; D055808:Drug Discovery; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D021381:Protein Transport; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D028961:beta Karyopherins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C424166:KPNB1 protein, human; D054852:Small Molecule Libraries; D014157:Transcription Factors; D028961:beta Karyopherins