Cyclin-Dependent Kinase (Cdk) Inhibitors
Cell cycle progression is regulated by a series of sequential events that include the activation and subsequent inactivation of cyclin dependent kinases (Cdks) and cyclins. Cdks are a group of serine/threonine kinases that form active heterodimeric complexes by binding to their regulatory subunits, cyclins. Eleven members of the Cdk family are reported so far, and each member of the family has a specific function in cell-cycle. Several Cdks, mainly Cdk2, Cdk4, and Cdk6, work cooperatively to drive cells from G1 phase into S phase. Cdk4 and Cdk6 are involved in early G1 phase, whereas Cdk2 is required to complete G1 phase and initiate S phase. Both Cdk4 and Cdk6 form active complexes with the D type of cyclins (cyclins D1, D2, and D3). Cdk2 is sequentially activated by the E type of cyclins, cyclins E1 and E2, during G1/S transition stage. A-type cyclins, cyclin A1 and A2, play a role during S phase. Cdk2/ cyclin A complex appears during late S phase and plays a role in progression of DNA replication. The cyclins that are involved in regulating the passage of the cell from the G2 checkpoint into M phase are known as mitotic cyclins and they associate with mitotic Cdks. Similarly, cyclins that are involved in the passage of cells from the G1 checkpoint into S phase are called G1 cyclins. Once the Cdks have completed their role, they undergo a rapid programmed proteolysis via ubiquitin-mediated delivery to the proteasome complex.
It is important to note here that Cdk5, a serinethreonine kinase, originally cloned from HeLa cells, is not directly involved in cell cycle. It is primarily active in neuronal tissue. Cdk5, in conjunction with its neuron-specific activator p35 (Cdk5/p35), has been implicated in tau hyperphosphorylation. Cdk5/p35 is also involved in neuronal migration and differentiation during development of the nervous system.
The enzymatic activity of a Cdk is regulated at three levels: cyclin association, subunit phosphorylation, and association with Cdk inhibitors. When cyclins initially bind to Cdks, the resulting complex is inactive. The phosphorylation of Cdks by Cdk activating kinases leads to their activation. Two main categories of Cdk inhibitors are reported in cells. They are the INK and the WAF/Kip families. The members of the INK family, INK4A (p16), INK4B (p15), INK4C (p18), and INK4D (p19), bind to Cdk4 and Cdk6 and block their interaction with D type cyclins thereby inhibiting Cdk activity. The members of the WAF/Kip family, WAF1 (p21), Kip1 (p27), and Kip2 (p57), form heterotrimeric complexes with the G1/S Cdks. Their major action is reported to be the inhibition of the kinase activity of Cdk/cyclin E complex.
From a therapeutic standpoint, Cdks are considered promising targets in cancer chemotherapy. The most promising strategies involve designing inhibitors that either block Cdk activity or prevent their interaction with cyclins. Most of the currently available molecules target the ATP-binding site of these enzymes. Such an approach might create serious problems as catalytic residues are well conserved across eukaryotic protein kinases. However, compounds such as Flavopiridol, Olomoucine, and Butyrolactone-1 that exhibit greater specificity for Cdks have shown promise.
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