Targeting the nuclear transport machinery by rational drug design.
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.
Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 116024, PR China.
Lei
L
Mao
Yongliang
Y
Yang
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D019295:Computational Biology; D015195:Drug Design; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D000097606:Exportin 1 Protein
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D028884:Karyopherins; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein