CDK9 a Potential Target for Drug Development

Abstract

The family of Cyclin-Dependent Kinases (CDKs) can be subdivided into two major functional groups based on their roles in cell cycle and/or transcriptional control. CDK9 is the catalytic subunit of positive transcription elongation factor b (P-TEFb). CDK9 is the kinase of the TAK complex (Tat-associated kinase complex), and binds to Tat protein of HIV, suggesting a possible role for CDK9 in AIDS progression. CDK9 complexed with its regulatory partner cyclin T1, serves as a cellular mediator of the transactivation function of the HIV Tat protein. P-TEFb is responsible for the phosphorylation of the carboxyl-terminal domain of RNA Pol II, resulting in stimulation of transcription. Furthermore, the complexes containing CDK9 induce the differentiation in distinct tissue. The CDK9/cyclin T1 complex is expressed at higher level in more differentiated primary neuroectodermal and neuroblastoma tumors, showing a correlation between the kinase expression and tumor differentiation grade. This may have clinical and therapeutical implications for these tumor types. Among the CDK inhibitors two have shown to be effective against CDK9: Roscovitine and Flavopiridol. These two inhibitors prevented the replication of human immunodeficiency virus (HIV) type 1 by blocking Tat transactivation of the HIV type 1 promoter. These compounds inhibit CDKs by binding to the catalytic domain in place of ATP, preventing transfer of a phosphate group to the substrate. More sensitive therapeutic agents of CDK9 can be designed, and structural studies can add information in the understanding of this kinase. The major features related to CDK9 inhibition will be reviewed in this article.

Flavopiridol induces phosphorylation of AKT in a human glioblastoma cell line, in contrast to siRNA-mediated silencing of Cdk9: Implications for drug design and development

“…11,12,56 Studies are underway to generate protein kinase inhibitors that are more specific for Cdk9-and Cdk7-related pathways, which both take part in the regulation of essential cellular processes, including cell survival and protection from apoptosis. 5,[8][9][10][11][12]40,[56][57][58][59][60][61][62] As anticipated, the complex Cdk9/cyclin T1 may promote the expression of anti-apoptotic PC3 prostate cancer cell line, followed by the other three human cell lines (Fig. 7).…”

“…In addition, the simultaneous inhibition of Cdk9-and Cdk7-related pathways might optimize the pharmacological targeting of malignant cells in cancer therapy. 5,40,[56][57][58][59][60][61][62] The discrepancy between the in vitro and in vivo models for Cdk9 and Cdk7-mediated phosphorylation of RNA pol II CTD may be related to a variety of factors. Of course, an in vitro system is rather artificial and does not always reproduces entirely the in vivo model.…”

“…5,40,[56][57][58][59][60][61][62] In our study, we evaluated the effects of siRNAmediated inhibition of Cdk9 and/or Cdk7 in a panel of human glioblastoma and human prostate cancer cell lines, which were compared with the effects of flavopiridol treatment. Substantial differences were found between the flavopiridol treatment and siRNA-mediated inhibition of Cdk9 and Cdk7 pathways.…”

SKIP counteracts p53-mediated apoptosis via selective regulation of p21Cip1 mRNA splicing

“…As a consequence, p53 is strongly induced in cells treated with P-TEFb/CDK9 inhibitors such as flavopiridol (FP). FP promotes apoptosis through induction of p53 and inhibition of short-lived anti-apoptotic proteins, and is currently in clinical trials as an anti-cancer agent for leukemia and solid tumors (Canduri et al 2008;Wang et al 2009). Thus, RNAPII is a genomewide sensor for DNA damage, through its ability to activate p53 and initiate programmed cell death upon encountering significant blocks to elongation.…”

Virtual Screening of CDK9 Inhibitors as Potential Anti Cancer Drugs

“…[8] CDK9 is a catalytic subunit of positive transcription elongation factor activated by either cyclin T or K. CDK9/T1 complex are highly expressed in nuero ectodermal and nueroblastoma tumors. [9] CDKs does not operate in isolation, a synergistic association with proteins called cyclins, catalyses the kinase activity of CDKs. After the association with cyclin, CDKs result in stimulating the transcription elongation of RNA pol II enzyme.…”