Blood Journal
Leading the way in experimental and clinical research in hematology

A small-molecule inhibitor of D-cyclin transactivation displays preclinical efficacy in myeloma and leukemia via phosphoinositide 3-kinase pathway

  1. Xinliang Mao1,2,
  2. Biyin Cao1,
  3. Tabitha E. Wood2,3,
  4. Rose Hurren2,
  5. Jiefei Tong4,
  6. Xiaoming Wang2,
  7. Wenjie Wang1,
  8. Jie Li1,
  9. Yueping Jin1,
  10. Wenxian Sun1,
  11. Paul A. Spagnuolo2,
  12. Neil MacLean2,
  13. Michael F. Moran4,5,
  14. Alessandro Datti6,7,
  15. Jeffery Wrana5,6,
  16. Robert A. Batey3,5, and
  17. Aaron D. Schimmer2,5
  1. 1Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, Suzhou, China;
  2. 2Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON;
  3. 3Department of Chemistry, The University of Toronto, Toronto, ON;
  4. 4Program in Molecular Structure and Function, Hospital for Sick Children, University of Toronto, Toronto, ON;
  5. 5McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, ON;
  6. 6Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; and
  7. 7Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy

Abstract

D-cyclins are universally dysregulated in multiple myeloma and frequently overexpressed in leukemia. To better understand the role and impact of dysregulated D-cyclins in hematologic malignancies, we conducted a high-throughput screen for inhibitors of cyclin D2 transactivation and identified 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161), which inhibited the expression of cyclins D1, D2, and D3 and arrested cells at the G0/G1 phase. After D-cyclin suppression, S14161 induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of leukemia, S14161 inhibited tumor growth without evidence of weight loss or gross organ toxicity. Mechanistically, S14161 inhibited the activity of phosphoinositide 3-kinase in intact cells and the activity of the phosphoinositide 3-kinases α, β, δ, and γ in a cell-free enzymatic assay. In contrast, it did not inhibit the enzymatic activities of other related kinases, including the mammalian target of rapamycin, the DNA-dependent protein kinase catalytic subunit, and phosphoinositide-dependent kinase-1. Thus, we identified a novel chemical compound that inhibits D-cyclin transactivation via the phosphoinositide 3-kinase/protein kinase B signaling pathway. Given its potent antileukemia and antimyeloma activity and minimal toxicity, S14161 could be developed as a novel agent for blood cancer therapy.

  • Submitted May 12, 2010.
  • Accepted November 27, 2010.
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