Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor

Abstract

The study describes the protein kinase selectivity profile, as well as the binding mode of olomoucine II in the catalytic cleft of CDK2, as determined from cocrystal analysis. Apart from the main cell cycle-regulating kinase CDK2, olomoucine II exerts specificity for CDK7 and CDK9, with important functions in the regulation of RNA transcription. In vitro anticancer activity of the inhibitor in a panel of tumor cell lines shows a wide potency range with a slight preference for cells harboring a wild-type p53 gene. Cell-based assays confirmed activation of p53 protein levels and events leading to accumulation of p21(WAF1). Additionally, in olomoucine II-treated cells, Mdm2 was found to form a complex with the ribosomal protein L11, which inhibits Mdm2 ubiquitin ligase function. We conclude that perturbations in RNA synthesis may lead to activation of p53 and that this contributes to the antiproliferative potency of cyclindependent kinase inhibitors.

Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance

“…Cytotoxicity and kinase specificity of BA-12 and BP-14 Novel derivatives of roscovitine, designated BA-12 and BP-14, were synthesized on the basis of our knowledge of structure-activity relationships for roscovitinerelated compounds (28,31). Cell viability assays showed strong cytotoxic effects of BA-12 and BP-14 on human HepG2 and PLC hepatoma cells (Fig.…”

Mitogen-activated Protein Kinase Kinase 1-dependent Golgi Unlinking Occurs in G2Phase and Promotes the G2/M Cell Cycle Transition

“…As expected, the Golgi ribbon was intact in S-phase cells, and green fluorescent protein (GFP)-labeled GalNacT2 rapidly recovered after photobleaching (Figure 6, A, C, and Supplemental Figure S3 movie). To accumulate late G 2 cells, thymidine washout was carried out in the presence of the CDK1 inhibitor olomoucine II (Krystof et al, 2005), which induced the expected arrest just before M phase (Keryer et al, 1998). Importantly, in late G 2 cells the ribbon was significantly fragmented (quantified below), and there was impaired fluorescence recovery even when the photobleaching was carried out on a region in proximity to other Golgi structures ( Figure 6, B and C, and Supplemental Figure S4 movie).…”

Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases

“…It phosphorylates the C-terminal domain of RNA polymerase II, regulating the elongation of mRNA transcription [33,34]. In cancer cells, antiproliferative effects of olomoucine II, representing the racemate of LGR561 and LGR556, via the inhibition of Cdk9 have already been determined [5,6].…”

“…Olomoucine, a 2, 6, 9-trisubstituted purine, represents one of the earliest reported specific Cdk inhibitors. Its discovery led to the development of more potent and Cdk-selective inhibitors such as roscovitine [3][4][5][6].…”