Serthr Kinase Inhibitors

Among the few hundred Ser/Thr kinases a handful are involved in transmitting the signals of upstream PTKs, and their activity is essential for cell proliferation and the onset of anti-apoptotic signaling (Fig. 7). Their abnormal enhanced activities are augmented by the deletion of negative regulators such as protein inhibitors of Cdks and the deletion of the tumor suppressor PTEN, the negative regulator of the PI3' kinase pathway. Thus, the activities of these kinases are enhanced by the synergistic action of the enhanced upstream PTKs combined with the inactivation of downstream negative regulators. As an example, Cdks execute the cell cycle and their activity has been found to be enhanced not only as a result of enhanced upstream signaling but also as a result of the overexpression of cyclin D1 and the deletion of Cdk inhibitors such as p15 and p16. Thus, Cdk2, Cdk1/Cdc2, and Cdk4 have become targets for new antineoplastic agents. Similarly, PI3' kinase signaling has been found to be enhanced by the deletion of its negative regulation PTEN. This deletion, characteristic of high-grade tumors, potentiates the already strong positive regulation of the PI3' kinase/PKB/mTor module complex by PTKs. Because of findings such as these, inhibitors of PKB and mTor are in development as antitumor agents.

Figure 8 Development of PKB/Akt inhibitors. One of the avenues to develop PKB inhibitors is to reverse the specificity of H-89, a PKA inhibitor. The advantage of this approach is the greater selectivity of the compound against other kinases and the relative simplicity of the experimental protocols.

PKB/Akt Inhibitors

Progress toward generation of PKB inhibitors (Aktstatins) has been recently reported [72]. In this study, the PKA inhibitor H-89 was modified to reduce its affinity to PKA but retaining and even improving its affinity to PKB/Akt (Fig. 8). Attempts are currently being made to widen the gap in selectivity towards PKB/Akt and increase the affinity.

Inhibitors of the Ras Pathway: Raf and Mek Inhibitors

Inhibitors of the Ras-Raf-Mek-Erk pathway have great therapeutic potential, as mutated Ras is the hallmark of many cancers. Mutated Ras occurs in 30% of all human tumors, in 80% of pancreatic cancers, in 50% of colorectal cancers, in 40% of lung cancer, and in 20% of hematopoietic malignancies. So far, no real success has been achieved in developing Ras inhibitors, but promising developments are reported in the development of Raf and Mek inhibitors. A recent study [73] shows that mutations that activate the kinase activity in B-Raf occur in « 66% of human melanomas, suggesting that Raf kinase inhibitors (such as the recently reported Onyx/Bayer compound BAY 43-9006 [74]) (Fig. 9) may be utilized to treat metastatic melanoma. Mek inhibitors such as PD 184352 [75] are also very promising. PD 184352 (Fig. 9) is a highly potent and selective inhibitor of Mek that is orally active. Tumor growth has been inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor [75]. Efficacy was achieved with a wide range of doses with no signs of toxicity and were correlated with a reduction in the levels of mitogen-activated protein kinase in excised tumors. These data indicate that Mek inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer. It is highly likely that many more inhibitors of this pathway will emerge in years to come.

Figure 9 Cdk, Raf, and Mek inhibitors.

PD 184352

Figure 9 Cdk, Raf, and Mek inhibitors.

Inhibitors of Cdks are being developed as anticancer agents [76-81]. Falvopiridol (Fig. 9) inhibits Cdk4/cyclin D and Cdk1/CyclinB1, with an IC50 value of 200 nM as compared to PKA and PKC, which it inhibits with IC50 of 960 |M and 10 |M, respectively [82]. This inhibitor is currently in clinical development (Table 1) [83].

PKC Inhibitors

Although we have been aware of PKC isozymes for a long time, little progress has been made in utilizing PKC inhibitors as therapeutic agents. Some agents are in development as anticancer drugs [77,84-86]. PKC-P inhibitors are also potential agents against vascular dysfunction [87] and are being evaluated as agents against vascular retinopa-thy, a complication of diabetes.


Rapamycin, the inhibitor of mTor, is effective as an inhibitor of angiogenesis and therefore is a potential anticancer drug [88]. Rapamycin is also effective in the inhibition of restenosis when applied on coated stents [89].


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