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. 1. Introduction Cyclin-dependent kinase 9 (CDK9) is a member of the cdc2-like serine/threonine kinase family and was identified in the early 1990s [1–3]. At that time, CDK9 was initially named PITALRE [1–3]. Overall, the Cdk9-related pathway comprises two isoforms termed CDK9-42 and CDK9-55 and four cyclin partners, such as cyclin T1, cyclin T2a, cyclin T2b, and cyclin K (Figure 1) (Table 1) [4–10]. The denominations 42 and 55 are related to the apparent molecular weight of the two CDK9 isoforms that were observed in Western blot analysis [4–10]. The noncovalent association between CDK9 and one of its cyclin partners gives rise to a heterodimer, in which CDK9 carries the enzymatic site and the cyclin functions as a regulatory subunit (Figure 2) [1–10]. The establishment of the heterodimer is essential to confer biological activity to the CDK9/cyclin partner complex [1–10]. The latter is quite stable [11]. This is in contrast to the monomeric CDK9, which is susceptible to a rather fast degradation [12]. For this reason, monomeric CDK9 molecules must form a transient complex with chaperone proteins HSP70, HSP90, and Cdc37, prior to the final association with the
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