Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic

Karyopherin beta 1 (Kpn beta 1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnb1 expression was found in certain cancers and Kpnb1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnb1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnb1 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 Kpn beta 1 and known Kpn beta 1 cargoes NFAT, NFkB, 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 Kpn beta 1. 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 Kpn beta 1 inhibitors could have therapeutic potential for the treatment of cancer. (C) 2016 AACR.