Inhibitors Of Serinethreonine Kinases

4.1. Cyclin-Dependent Kinases

Cyclin-dependent kinases (CDKs) are involved in the control of the cell cycle, being in charge of moving the cell cycle from one phase to the next. CDKs are activated by complexation with a group of associated proteins called cyclins. There are several types of cyclins and CDKs that play their roles at different stages of the cell cycle. For instance, in the G1 phase, an increase in cyclin D followed by its binding to CDK4 and CDK6 leads to the phosphorylation of the tumor suppressor protein known as retinoblastoma (pRB). This molecule is normally bound to the transcription factor, E2F which is thereby inactivated. Phosphorylation of pRB prevents this binding, leaving the transcription factor free to bind to DNA, leading to the synthesis of several proteins, including cyclin E, which binds to CDK2 and the complex is necessary for the progression from the G1 to the S phase. Other complexes that are required for the progression of the cell cycle through subsequent stages are cyclin E-CDK2 and cyclin B-CDK1 (Fig. 9.15). On the other hand, the cell cycle is down-regulated by CDK inhibitors, also known as CKIs (p15, p21), which are proteins that restrain the activity of CDKs. Over-activity of cyclins or CDKs or insufficient activity of CKIs is associated with several tumors, making these processes attractive anticancer57 and antiviral58 targets.

Several structurally varied competitive inhibitors of CDKs have been developed, and some of them are in clinical trials, including flavopiridol, roscovitine, BMS-387032, and indisulam (E-7070).

FIGURE 9.15 Control of cell cycle by cyclins and CDKs.
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