American Association for Cancer Research
15357163mct150052-sup-144191_2_supp_3265060_nz70vy.pptx (107.25 kB)

Supplementary figure 3 from Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic

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posted on 2023-04-03, 14:21 authored by Pauline J. van der Watt, Alicia Chi, Tamara Stelma, Catherine Stowell, Erin Strydom, Sarah Carden, Liselotte Angus, Kate Hadley, Dirk Lang, Wei Wei, Michael J. Birrer, John O. Trent, Virna D. Leaner

Body mass graphs from in vivo studies showing no change in body weight over the treatment time-courses.


the South African Medical Research Council, the National Research Foundation, the Cancer Association of South Africa (CANSA), and the University of Cape Town



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.

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