Characterization of a novel cyclin-dependent kinase 1 inhibitor, BMI-1026.
Cyclin-dependent kinases (Cdks) have been attractive targets for the development of anticancer therapeutic agents. In an effort to generate a new class of anti-Cdk inhibitors, we synthesized aryl aminopyrimidines and examined the effect of these compounds in both in vitro kinase assays and cultured cells. Two of these compounds, BMI-1026 and BMI-1042, induced a strong cell cycle alteration with potent inhibitory activities against cyclin-dependent kinases, collectively known as Cdks. Characterization of BMI-1026 revealed that it imposes a potent G(2)-M arrest and mild G(1)-S and S arrests. In vitro biochemical analyses and in vivo time-lapse microscopy studies revealed that it induces a mitotic catastrophe and precocious mitotic exit even in the presence of nocodazole. These defects appeared to lead to apoptotic cell death in tumorigenic cell lines. Consistent with the induction of mitotic defects and apoptosis, BMI-1026 imposed a selective sensitivity to proliferating versus differentiating or growth-arrested mouse keratinocytes. These data suggest that BMI-1026 could be developed as a potential anti-Cdk1 chemotherapeutic agent.
Seong
Yeon-Sun
YS
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH. Bethesda, Maryland 20892, USA.
Min
Changhee
C
Li
Luowei
L
Yang
Jae Young
JY
Kim
Soo-Yeon
SY
Cao
Xiaodong
X
Kim
Keetae
K
Yuspa
Stuart H
SH
Chung
Hyun-Ho
HH
Lee
Kyung S
KS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010636:Phenols / Q000138:chemical synthesis / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D010636:Phenols; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000097869:Polo-Like Kinase 1; C480542:BMI 1026