Kpn{beta}1 as an Anticancer Target

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, NFB, 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.

Source: Molecular Cancer Therapeutics - April 4, 2016 Category: Cancer & Oncology Authors: van der Watt, P. J., Chi, A., Stelma, T., Stowell, C., Strydom, E., Carden, S., Angus, L., Hadley, K., Lang, D., Wei, W., Birrer, M. J., Trent, J. O., Leaner, V. D. Tags: Small Molecule Therapeutics Source Type: research