Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells

• DOI: 10.1038/leu.2012.219
• Publication Date: 2012-07-31T08:20:29Z
• Authors: J Etchin; Q Sun; A Kentsis; A Farmer; Z C Zhang; T Sanda; M R Mansour; C Barcelo; D McCauley; M Kauffman; S Shacham; A L Christie; A L Kung; S J Rodig; Y M Chook; A T Look
• Keywords: Nuclear export signal

Drugs that target the chief mediator of nuclear export, chromosome region maintenance 1 protein (CRM1) have potential as therapeutics for leukemia, but existing CRM1 inhibitors show variable potencies and a broad range cytotoxic effects. Here, we report structural analysis antileukemic activity new generation small-molecule CRM1. Designated selective export (SINE), these compounds were developed using molecular modeling to screen small virtual library against signal (NES) groove The 2.2-Å crystal structure CRM1-Ran-RanBP1 complex bound KPT-251, representative molecule this class inhibitors, shows drug occupies part in is usually occupied by NES, penetrates much deeper into blocks CRM1-directed export. SINE exhibit potent activity, inducing apoptosis at nanomolar concentrations panel 14 human acute myeloid leukemia (AML) cell lines representing different subtypes disease. When administered orally immunodeficient mice engrafted with AML cells, KPT-251 had negligible toxicity normal hematopoietic cells. Thus, KPT-SINE antagonists represent novel drugs warrant further testing patients.