J

Activates by phosphorylation

Increases

Ribosomal RNA and ribonucleoprotein synthesis

Increases

Cyclin D synthesis

FIGURE 9.20 Activation of cyclin D synthesis involving PI3K, PDK1( AKT and mTOR kinases.

Association of these inhibitors with compounds targeting AKT-associated kinases, such as CSNK1G3 and/or IPMK has been suggested as a way to achieve increased efficacy and improved therapeutic index.77

Inhibition of heat-shock protein 90 (HSP 90) provides a third, indirect way to achieve AKT inhibition,74 and will be discussed in Section 7.

4.2.2. PDK1 inhibitors

UCN-01 is a natural staurosporine derivative that was originally described as a selective inhibitor of PKC, but further research showed that it is non-specific; for instance, it is a potent inhibitor of CDKs, checkpoint kinase 1 (CHK-1) and PKC. However, its antitumor activity seems to be related to CHK-1 inhibition78 and to disruption of the PI3K-AKT pathway through inhibition of PDK1.79 UCN-01 is currently under clinical development.80

H3CO

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