Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells Academic Article uri icon

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abstract

  • Abstract We tested the effects of small-molecule XIAP antagonists based on a polyphenylurea pharmacophore on cultured acute myelogenous leukemia (AML) cell lines and primary patient samples. X-linked inhibitor of apoptosis protein (XIAP) antagonist N-[(5R)-6-[(anilinocarbonyl)amino]-5-((anilinocarbonyl){[(2R)-1-(4-cyclohexylbutyl)pyrrolidin-2-yl]methyl}amino)hexyl]-N-methyl-N′-phenylurea (1396-12), but not a structurally related control compound, induced apoptosis of primary leukemia samples with a lethal dose (LD50) of less than 10 μM in 16 of 27 (60%) samples. In contrast, XIAP antagonist 1396-12 was not lethal to the normal hematopoietic cells in short-term cytotoxicity assays. Response of primary AML specimens to XIAP inhibitor correlated with XIAP protein levels, with higher levels of XIAP associated with sensitivity. The XIAP antagonist 1396-12 induced activation of downstream caspases 3 and 7 prior to the activation of upstream caspase 8 and caspase 9. Apoptosis induction was also independent of B-cell lymphoma protein-2 (Bcl-2) or caspase 8, indicative of a downstream effect on apoptotic pathways. Thus, polyphenylurea-based XIAP antagonsists directly induce apoptosis of leukemia cells and AML patient samples at low micromolar concentrations through a mechanism of action distinct from conventional chemotherapeutic agents.

authors

  • Carter, Bing Z
  • Gronda, Marcela
  • Wang, Zhiliang
  • Welsh, Kate
  • Pinilla, Clemencia
  • Andreeff, Michael
  • Schober, Wendy D
  • Nefzi, Adel
  • Pond, Gregory
  • Mawji, Imtiaz A
  • Houghten, Richard A
  • Ostresh, John
  • Brandwein, Joseph
  • Minden, Mark D
  • Schuh, Andre C
  • Wells, Richard A
  • Messner, Hans
  • Chun, Kathy
  • Reed, John C
  • Schimmer, Aaron D

publication date

  • May 15, 2005

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