A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma.
The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive. Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells. In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre-T-LBL.
Lin
Ying-Wei
YW
Department of Pediatrics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Beharry
Zanna M
ZM
Hill
Elizabeth G
EG
Song
Jin H
JH
Wang
Wenxue
W
Xia
Zuping
Z
Zhang
Zhenhua
Z
Aplan
Peter D
PD
Aster
Jon C
JC
Smith
Charles D
CD
Kraft
Andrew S
AS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D045162:Thiazolidinediones / Q000494:pharmacology*
D001597:Benzylidene Compounds; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; C490587:PIM2 protein, human; C094167:Pim2 protein, mouse; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C000622607:SMI-4a compound; D045162:Thiazolidinediones; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C496634:PIM1 protein, human; C499249:PIM3 protein, human; C496636:Pim1 protein, mouse; C488192:Pim3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases