several cycline dependent kinase 2 (cdk2) inhibitors with different chemical structures have been introduced. the hinge region of cdk2 (residues 81–84) contains a set of hydrogen bond donor and acceptor sites some of which must be satisfied for potent inhibitor binding. the benzimidazolone skeleton may provide such interactions. accordingly, 3-sulfonamide substituted benzamido-benzimidazolones ...

Abstract Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods We used the combination computational experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for treatment HCC. Results identified vanoxerine dihydrochloride a...

BACKGROUND Cyclin-dependent kinases (Cdks) and their cyclin regulatory subunits control cell growth and division. Cdk2/cyclin E complexes are thought to be required because they phosphorylate the retinoblastoma protein and drive cells through the G1/S transition into the S phase of the cell cycle. In addition, Cdk2 associates with cyclin A, which itself is essential for cell proliferation durin...

Abstract In mammalian cells, the decision to proliferate is thought be irreversibly made at restriction point of cell cycle 1,2 , when mitogen signalling engages a positive feedback loop between cyclin A2/cyclin-dependent kinase 2 (CDK2) and retinoblastoma protein 3–5 . Contrary this textbook model, here we show that actually fully reversible. Instead, find all cycling cells will exit in absenc...

Cell-cycle regulatory protein, CDK2 is active when bound to its complementary partner protein, CyclinA or E. Recent discovery of the Kip/Cip family of proteins has indicated that the activity of CDK2 is also regulated by a member protein, p27. Although, the mechanism of CDK2 inhibition by p27 binding is known from crystal structure, little is known about the mechanism of CDK2 reactivation. Here...

Cdc45 is required for initiation of DNA replication and fork progression, but its function in these processes remains unknown. We show that targeting Cdc45 to specific chromosomal sites in mammalian cells results in large-scale chromatin decondensation that strongly correlates with histone H1 phosphorylation. Cdk2 is recruited to sites of Cdc45 decondensation, and Cdk2 inhibitors reduce the lev...

Proliferation of oligodendrocyte progenitor (OP) cells is a crucial process controlling myelination in the CNS. Previous studies demonstrated a correlation between OP proliferation rate and cyclin E/cyclin-dependent kinase-2 (cdk2) activity. To establish a causal link between cyclin E/cdk2 activity and OP proliferation, we selectively modulated cdk2 activity in vitro by transfection of cultured...

Cyclin-dependent kinase 2 (CDK2) is a promising target for cancer treatment, developing new effective CDK2 inhibitors of great significance in anticancer therapy. The involvement tumorigenesis has been debated, but recent evidence suggests that specifically inhibiting could be beneficial treating certain tumors. This approach remains attractive the development drugs. Several small-molecule targ...

Cyclin dependent kinases (cdks) regulate cell cycle progression and transcription. We report here that the transcriptional co-activator PCAF directly interacts with cdk2. This interaction is mainly produced during S and G(2)/M phases of the cell cycle. As a consequence of this association, PCAF inhibits the activity of cyclin/cdk2 complexes. This effect is specific for cdk2 because PCAF does no...