Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells.
The Pim protein kinases play important roles in cancer development and progression, including prostate tumors and hematologic malignancies. To investigate the potential role of these enzymes as anticancer drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function as potent Pim protein kinase inhibitors. With IC(50) values in the nanomolar range, these compounds block the ability of Pim to phosphorylate peptides and proteins in vitro and, when added to DU145 prostate cancer cells overexpressing Pim, inhibit the ability of this enzyme to phosphorylate a known substrate, the BH(3) protein BAD. When added to prostate cancer cell lines, including PC3, DU145, and CWR22Rv1, and human leukemic cells, MV4;11, K562, and U937 cells, these compounds induce G(1)-S cell cycle arrest and block the antiapoptotic effect of the Pim protein kinase. The cell cycle arrest induced by these compounds is associated with an inhibition of cyclin-dependent kinase 2 and activity and translocation of the Pim-1 substrate p27(Kip1), a cyclin-dependent kinase 2 inhibitory protein, to the nucleus. Furthermore, when added to leukemic cells, these compounds synergize with the mammalian target of rapamycin inhibitor rapamycin to decrease the phosphorylation level of the translational repressor 4E-BP1 at sites phosphorylated by mammalian target of rapamycin. Combinations of rapamycin and the benzylidene-thiazolidine-2,4-diones synergistically block the growth of leukemic cells. Thus, these agents represent novel Pim inhibitors and point to an important role for the Pim protein kinases in cell cycle control in multiple types of cancer cells.
Beharry
Zanna
Z
Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
Zemskova
Marina
M
Mahajan
Sandeep
S
Zhang
Fengxue
F
Ma
Jian
J
Xia
Zuping
Z
Lilly
Michael
M
Smith
Charles D
CD
Kraft
Andrew S
AS
D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells; D051025:bcl-Associated Death Protein / Q000378:metabolism
D001597:Benzylidene Compounds; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D045162:Thiazolidinediones; D051025:bcl-Associated Death Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim