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.