A small-molecule inhibitor of D-cyclin transactivation displays preclinical efficacy in myeloma and leukemia via phosphoinositide 3-kinase pathway.
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.
Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, Suzhou, China. xinliangmao@suda.edu.cn
Xinliang
X
Mao
Biyin
B
Cao
Tabitha E
TE
Wood
Rose
R
Hurren
Jiefei
J
Tong
Xiaoming
X
Wang
Wenjie
W
Wang
Jie
J
Li
Yueping
Y
Jin
Wenxian
W
Sun
Paul A
PA
Spagnuolo
Neil
N
MacLean
Michael F
MF
Moran
Alessandro
A
Datti
Jeffery
J
Wrana
Robert A
RA
Batey
Aaron D
AD
Schimmer
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D056741:Cyclin D / Q000037:antagonists & inhibitors* / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D041681:NIH 3T3 Cells; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
C557120:8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene; D000970:Antineoplastic Agents; D001578:Benzopyrans; D056741:Cyclin D; D017931:DNA Primers; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt