The in vitro and in vivo effects of JNJ-7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases.
Modulation of aberrant cell cycle regulation is a potential therapeutic strategy applicable to a wide range of tumor types. JNJ-7706621 is a novel cell cycle inhibitor that showed potent inhibition of several cyclin-dependent kinases (CDK) and Aurora kinases and selectively blocked proliferation of tumor cells of various origins but was about 10-fold less effective at inhibiting normal human cell growth in vitro. In human cancer cells, treatment with JNJ-7706621 inhibited cell growth independent of p53, retinoblastoma, or P-glycoprotein status; activated apoptosis; and reduced colony formation. At low concentrations, JNJ-7706621 slowed the growth of cells and at higher concentrations induced cytotoxicity. Inhibition of CDK1 kinase activity, altered CDK1 phosphorylation status, and interference with downstream substrates such as retinoblastoma were also shown in human tumor cells following drug treatment. Flow cytometric analysis of DNA content showed that JNJ-7706621 delayed progression through G1 and arrested the cell cycle at the G2-M phase. Additional cellular effects due to inhibition of Aurora kinases included endoreduplication and inhibition of histone H3 phosphorylation. In a human tumor xenograft model, several intermittent dosing schedules were identified that produced significant antitumor activity. There was a direct correlation between total cumulative dose given and antitumor effect regardless of the dosing schedule. These results show the therapeutic potential of this novel cell cycle inhibitor and support clinical evaluation of JNJ-7706621.
Emanuel
Stuart
S
Cancer Therapeutics Research, Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, New Jersey 08869, USA. semanuel@prdus.jnj.com
Rugg
Catherine A
CA
Gruninger
Robert H
RH
Lin
Ronghui
R
Fuentes-Pesquera
Angel
A
Connolly
Peter J
PJ
Wetter
Steven K
SK
Hollister
Beth
B
Kruger
Walter W
WW
Napier
Cheryl
C
Jolliffe
Linda
L
Middleton
Steven A
SA
D000818:Animals; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C506121:JNJ-7706621; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases