The Karyopherin superfamily consists of seven known proteins that mediate the majority of transport of molecules through the nuclear pores in a cell nucleus.
One of these proteins: chromosome region maintenance1 (CRM1, aka XPO1 or exportin1) is a key transporter protein that exports cargo from within the cell nucleus out to the cytoplasm. The role of CRM1 is to export tumor suppressor proteins and growth regulatory proteins.
Over-expression of CRM1 has been found in various malignancies and leads to mislocalization of several growth and survival factors. Inhibiting CRM1 leads to an accumulation of tumor suppressor proteins, which eventually triggers apoptosis, killing off the problem causing cell. CRM1 also plays an important role in viral replication. Preventing this protein, which the virus is dependent on for survival, to function should then prevent the virus from replicating, effectively shutting it down.
Lab studies have found that the CRM1 inhibitor KPT-276 shows activity against several types of cancer, including glioblastoma, lung cancer, and breast cancer, among others.
Studies on the CRM1 inhibitor verdinexor have shown that these inhibitors also act as antiviral agents. Both in vitro and in vivo studies have demonstrated the antiviral benefit of a treatment based on CRM1 inhibition, particularly in the face of the drug resistance that has developed against common antiviral drugs.
The CRM1 inhibitors KPT-276 and Verdinexor are now available from LKT Laboratories for further research use.
References
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Cheng Y, Holloway MP, Nguyen K, et al. XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer. Mol Cancer Ther. 2014 Mar; 13(3):675-686. doi: 10.1158/1535-7163.MCT-13-0416.
Wang S, Han X, Wang J, et al. Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. PLoS One. 2014 Mar 4;9(3):e89848. doi: 10.1371/journal.pone.0089848
Green Al, Ramkissoon SH, McCauley D, et al. Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma. Neuro Oncol. 2015 May;17(5):697-707. doi: 10.1093/neuonc/nou303.
Lundberg L, Pinkham C, de la Fuente C, et al. Selective inhibitor of nuclear export (SINE) compounds alter new world alphavirus capsid localization and reduce viral replication in mammalian cells. PLoS Negl Trop Dis. 2016 Nov 30;10(11):e0005122. doi: 10.1371/journal.pntd.0005122.
Perwitasari O, Johnson S, Yan X, et al. Antiviral efficacy of verdinexor in vivo in two animal models of influenza A virus infection. PLoS One. 2016 Nov 28;11(11):e0167221. doi: 10.1371/journal.pone.0167221.