Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells

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

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)66-74
Number of pages9
JournalLeukemia
Volume27
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Cell Nucleus Active Transport
Nuclear Export Signals
Acute Myeloid Leukemia
Myeloid Cells
Digital Libraries
Pharmaceutical Preparations
exportin 1 protein
Leukemia
Apoptosis
Cell Line

Keywords

  • AML
  • CRM1
  • nuclear export inhibitors

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Etchin, J., Sun, Q., Kentsis, A., Farmer, A., Zhang, Z. C., Sanda, T., ... Look, A. T. (2013). Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia, 27(1), 66-74. https://doi.org/10.1038/leu.2012.219

Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. / Etchin, J.; Sun, Q.; Kentsis, A.; Farmer, A.; Zhang, Z. C.; Sanda, T.; Mansour, M. R.; Barcelo, C.; McCauley, D.; Kauffman, M.; Shacham, S.; Christie, A. L.; Kung, A. L.; Rodig, S. J.; Chook, Y. M.; Look, A. T.

In: Leukemia, Vol. 27, No. 1, 01.2013, p. 66-74.

Research output: Contribution to journalArticle

Etchin, J, Sun, Q, Kentsis, A, Farmer, A, Zhang, ZC, Sanda, T, Mansour, MR, Barcelo, C, McCauley, D, Kauffman, M, Shacham, S, Christie, AL, Kung, AL, Rodig, SJ, Chook, YM & Look, AT 2013, 'Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells', Leukemia, vol. 27, no. 1, pp. 66-74. https://doi.org/10.1038/leu.2012.219
Etchin J, Sun Q, Kentsis A, Farmer A, Zhang ZC, Sanda T et al. Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia. 2013 Jan;27(1):66-74. https://doi.org/10.1038/leu.2012.219
Etchin, J. ; Sun, Q. ; Kentsis, A. ; Farmer, A. ; Zhang, Z. C. ; Sanda, T. ; Mansour, M. R. ; Barcelo, C. ; McCauley, D. ; Kauffman, M. ; Shacham, S. ; Christie, A. L. ; Kung, A. L. ; Rodig, S. J. ; Chook, Y. M. ; Look, A. T. / Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. In: Leukemia. 2013 ; Vol. 27, No. 1. pp. 66-74.
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