Deregulations in the cyclin-dependent kinase-9-related pathway in cancer: implications for drug discovery and development

Abstract

The CDK9-related pathway is an important regulator of mammalian cell biology and is also involved in the replication cycle of several viruses, including the human immunodeficiency virus type 1. CDK9 is present in two isoforms termed CDK9-42 and CDK9-55 that bind noncovalently type T cyclins and cyclin K. This association forms a heterodimer, where CDK9 carries the enzymatic site and the cyclin partner functions as a regulatory subunit. This heterodimer is the main component of the positive transcription elongation factor b, which stabilizes RNA elongation via phosphorylation of the RNA pol II carboxyl terminal domain. Abnormal activities in the CDK9-related pathway were observed in human malignancies and cardiac hypertrophies. Thus, the elucidation of the CDK9 pathway deregulations may provide useful insights into the pathogenesis and progression of human malignancies, cardiac hypertrophy, AIDS and other viral-related maladies. These studies may lead to the improvement of kinase inhibitors for the treatment of the previously mentioned pathological conditions. This review describes the CDK9-related pathway deregulations in malignancies and the development of kinase inhibitors in cancer therapy, which can be classified into three categories: antagonists that block the ATP binding site of the catalytic domain, allosteric inhibitors, and small molecules that disrupt protein-protein interactions.

Figure 1

This figure displays the binding partners for Cdk9: cyclin K, cyclin T1, and cyclin T2a. Cyclin T2b is very similar to cyclin T2a and is not shown. Abbreviation: PHE: phenylalanine.

Figure 2

The Cdk9/cyclin T1 complex. The arrow depicts a yellow line, which shows the binding interface between Cdk9 and cyclin T1.

Figure 3

The components of the CDK9-related pathway.

Figure 4

This figure describes the role of the P-TEFb complex in stabilizing RNA elongation. Panel (a) illustrates a nonpermissive state for RNA elongation. In this configuration, RNA pol II is associated with N-TEF, and the RNA pol II CTD is not phosphorylated. In this case, RNA transcription can start but stops prematurely. Panel (b) shows a state of transition, in which P-TEFb is about to substitute N-TEF in the transcription complex. P-TEFb contains the complex Cdk9/cyclin partner. Panel (c) exhibits a permissive state for RNA elongation. The presence of P-TEFb in the transcription complex phosphorylates the RNA pol II CTD, which, in turn, allows for the stabilization of the RNA transcript elongation. Abbreviations: RNA pol II: RNA polymerase II; N-TEF: negative transcription factor; CTD: carboxyl terminal domain of RNA pol II; P-TEFb: positive transcription factor b.