CDK Inhibition

Although designing drugs for restoring pRb binding to, and repression of, E2F would be extremely difficult, the G1 cyclin-cdk complexes appear to be good candidates for rational drug design. Preventing hyperphosphorylation of pRb should block the cell from breaching the restriction point, preventing cell-cycle progression. The inhibition of the G1 cyclin-cdk complexes can be targeted in two distinct ways. The most obvious method of inhibition is the direct inhibition of the desired cyclin-cdk complex, but a second method of cyclin/cdk inhibition, analogous to the effect of the Cip/Kip p21 on cyclin B/Cdk1, seeks to inhibit the cyclin/cdk activation by CAK or prevent inhibition by Wee1.23 Many cdk inhibitors have been developed, with varying degrees of specificity for individual cdks. In general, these inhibitors tend to inhibit other cellular kinases as well as cdks, and the design of absolutely specific cdk inhibitors is not imperative, providing that nonspecific inhibitors are effective treatments. Currently the most promising cdk inhibitors in clinical trials are flavopiridol and UCN-01, both of which are nonspecific cdk inhibitiors.

Flavopiridol inhibits a broad spectrum of cdks by acting as a competitive inhibitor of ATP for the binding pocket of cdks.23 Although the inhibitory effect of flavopiridol on most cdks can be competed away by the addition of excess ATP, the inhibitory effect of flavopiridol on cyclin T/Cdk9 cannot be competed away by the addition of excess ATP, making the exact mechanism of inhibition of cyclin T/Cdk9 unclear. Additionally, flavopiridol appears to be more specific for a subset of cdks because it is less potent in its inhibition of cdk7 (CAK). Cell-cycle arrests from flavopiridol can result at either the G1-S transition or the G2-M transition. As expected, the G1-S transition results in part from the direct inactivation of Cdk4/6/2, but flavopiridol also reduces CYCLIN D1 expression and inhibits activation of G1 cdks by CAK.23 The inhibition of CAK can also result in the G2-M arrest.

UCN-01 causes cell-cycle arrest in a different manner from flavopiridol, regulating the activity of cdks indirectly at low concentrations.23 Created by rational design from stau-rosporine, a nonspecific kinase inhibitor, UCN-01 affects several kinase targets, including PKC, cdks, Weel, and PDK1.23 Although UCN-01 only directly inhibits cdks at high concentrations, it has an antiproliferative effect that functions in part through its inhibition of Weel. Blocking Weel activity leads to increased activation of Cdkl, causing premature entry into mitosis and apoptosis. Recent research also indicates that UCN-01 can inhibit PDK1, which may contribute to the antiproliferative effects. PDK1 activates Akt by phosphorylation, so inhibition of PDK1 would prevent Akt from inactivating the forkhead family of transcription factors. Although UCN-01 affects cdk regulation through Wee1, the drug clearly has off targets, such as PDK1, which may contribute to its success or failure as a chemotherapeutic agent.

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