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A Small-Molecule Inhibitor of D-cyclin Transactivation Displays Preclinical Efficacy in Myeloma and Leukemia via Phosphoinositide 3-kinase Pathway

A Small-Molecule Inhibitor of D-cyclin Transactivation Displays Preclinical Efficacy in Myeloma and Leukemia via Phosphoinositide 3-kinase Pathway

Xinliang Mao, Biyin Cao, Tabitha E Wood, Rose Hurren, Jiefei Tong, Xiaoming Wang, Wenjie Wang, Jie Li, Yueping Jin, Wenxian Sun, Paul A Spagnuolo, Neil MacLean, Michael F Moran, Alessandro Datti, Jeffery Wrana, etc.

Blood. 2011 Feb 10;117(6):1986-97.

PMID: 21135258

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 G(0)/G(1) 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP883046502	S14161		883046-50-2	Price

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