Targeting the Nuclear Transport Machinery by Rational Drug Design

Lei      Mao; Yongliang      Yang

doi:10.2174/1381612811319120018

Abstract

CRM1 (also referred as exportin1 or Xpo1) is a key member of the importin β superfamily of nuclear transport receptors. Its potential as therapeutic target has attracted significant attention in recent years. CRM1 controls the transport of a number of growth regulatory proteins and tumor suppressor proteins including p53, p21, FOXO, PI3K/AKT, Wnt/ß-catenin, AP-1 and NF-kB etc. The overexpression of CRM1 has been found to correlate with a variety of neoplastic conditions such as pancreatic and liver cancer. In addition, CRM1 could mediate the transport of viral proteins such as Rev, an essential factor protein for HIV replication. Moreover, CRM1 has been implicated in key steps of mitosis during cell cycles. Over the past years, the in-depth biological studies have rendered CRM1 as a promising clinical target. The interference of CRM1-mediated transport machinery could lead to the effective treatment of a variety of human disease related to cell proliferation. The aim of this paper is to summarize the research progress of CRM1 inhibitors in the late 30 years. More importantly, we want to provide new insights for the CRM1 drug design from the perspective of molecular simulation.

Keywords: CRM1 inhibitors, nuclear protein transport, rational drug design, molecular simulation, mitosis, cell cycles, cell proliferation, viral proteins, Rev, clinical target