PDKl inhibitors

Contrary to the other major components of the PI3K/PKB survival pathway, the development of PDKl inhibitors would be, to a certain extent, simpler as only a single PDKl isoform exists in human cells. Moreover, the observation that PDKl hypomorphic mice expressing only approximately 10% of the normal level of PDKl display no obvious harmful phenotype—they are 40-50% smaller than control animals — [100], indicates that a PDKl inhibitor may provide effective anticancer therapy at an acceptable therapeutic index. 

In addition to pulmonary toxicity, nausea/vomiting, lactic acidosis and transaminitis, UCN-01 induced insulin resistance during Phase I clinical trials. As shown recently with rat adipose cells, this effect may be due to UCN-01 inhibition of PKB Thr-308 phosphorylation—no effect on Ser-473 was observed in this study—and subsequent blockade of GLUT4 translocation in response to insulin [104]. If this mode of action is confirmed in the ongoing clinical trials and contrary to what was observed in the PDKl hypomorphic mice (vide supra) [100], insulin resistance may represent an important hurdle in the development of PDKl inhibitors and, in general, of any agent that blocks the PI3K/PKB pathway in adipose and muscle cells. 

In addition to UCN-01 and other staurosporine or maleimide derivatives (e.g., compounds 17 and 18 Fig. 4) [102,103,105-107], PDKl kinase activity is inhibited by aminopyrimidines. A representative example of this compound class is BX-320 (compound 19, Fig. 4), a PDKl inhibitor (IC50 = 30 nM) that displays good selectivity over protein kinase A (PKA, 35-fold) [108]. BX-320 blocks the growth in soft agar of a wide range of tumor cell lines (IC50 = 0.093 to 1.32 xM), and shows efficacy in a metastasis mouse model (200 mg/kg bid). 

Selective 3-phosphoinositide-dependent kinase 1 (PDKl) inhibitors Dissecting the function and pharmacology of PDKl 13JMC2726. Staurosporine analogues from microbial and synthetic sources and their biological activities 13CMD3872. 

Abbott and colleagues found that catalytic hydrogenation achieves their desired goal (equation 4) in a project targeted at new PDKl inhibitors [88],... 

CDK2 activity of 4.1 [iM consistent with the reduced CDK2 activity of 5-substituted pyrimidines like 77. Compound 89 had a PDKl IC50 of 0.39 pM and later became a lead for a PDKl inhibitor program. ... 

The most potent PDKl kinase inhibitor reported to date is UCN-01 (compound 16 Fig. 4 IC50 = 6 to 33 nM) [101], a staurosporine analogue isolated from the culture broth of Streptomyces sp. Originally developed as an inhibitor of calcium-dependent PKC, UCN-01 has the capacity to inhibit a broad spectrum of kinases [102], including other members of the AGC subfamily of kinases (e.g., IC5o = 491nM for PKB) [103]. UCN-Ol-induced PDKl inhibition has also been observed in in vivo murine and human tumor xenografts [101]. 

Figure 50. PTEN. The tumor suppressor gene and gene product protein PTEN (phosphatase tensin homolog deleted on chromosome ten, human 10q23.3) (Table VIII), is the natural inhibitor of oncogenes PI3K/Akt (phosphatidyl inositol kinase 3 protein kinase 3 phosphatidylinositol 3 phosphate Jacob Furth s AK mouse strain thymic lymphoma retroviral oncogene phosphoinosite-dependent kinase). The PTEN protein inactivates PIP3 by dephosphorylation PDKl (phosphoinositol-dependent kinase) is not recruited to the plasma membrane to activate Akt by phosphorylation. Sarah M. Planchon et al. The nuclear affairs of PTEN. J Cell Sci 2008 121 249-253. doi 10.1242/jcs.022459...

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