Journal
CANCER RESEARCH
Volume 66, Issue 1, Pages 435-444Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-05-1769
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Funding
- NATIONAL CANCER INSTITUTE [P20CA090578, R01CA090687] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA090687, R01 CA90687, P20 CA90578] Funding Source: Medline
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Preclinical studies were performed of a novel selective imidazopyridine cyclin-dependent kinase (cdk) inhibitor, AZ703. In vitro kinase assays showed that IC50 values for AZ703 against purified cyclin E/cdk2 and cyclin B/cdk1 were 34 and 29 nmol/L, respectively. In contrast, the IC50 against cdk4 was > 10 mu mol/L. AZ703 also inhibited cdk7 and cdk9 with IC50 values of 2.1 mu mol/L and 521 nmol/L, respectively. Treatment of U20S, NCl-H1299, and A549 cells for 24 hours resulted in growth arrest involving multiple cell cycle phases. At low drug concentrations (< 2 mu mol/L), G(2) arrest predominated, whereas at higher concentrations (>= 2 mu mol/L), S-G(2) arrest was observed. When cells were synchronized in G, by starvation and released into AZ703, a block in G, occurred that was not evident in exponentially growing cells. Cell cycle arrest was associated with reduced phosphorylation of the retinoblastoma protein and p27(Kip1) at cdk2 phospho-sites. Following longer exposures, apoptosis was evident. Cells were further sensitized to AZ703 following recruitment to S phase by synchronization. Consistent, with the inhibition of cdks during S and G2 that modulate the activity and stability of E2F-1, AZ703 treatment induced E2F-1 expression. In U20S and NCl-H1299 cells engineered to inducibly express the dominant-negative mutant E2F-1 (1-374), expression of the mutant decreased AZ703-mediated apoptosis, indicating dependence on E2F-1 transcriptional targets. AZ703-induced apoptosis in NCl-HI299 cells was enhanced by small interfering RNA-mediated depletion of cdk9, which caused reduced levels of Mcl-1 and XIAP, suggesting that cdk2, cdk1, and cdk9 represent a rational subset of family members for drug targeting.
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