AKT kinase inhibitors

Scheme 6.261 Synthesis of quinoxalines as allosteric Akt kinase inhibitors.

In the synthesis of a compound library of allosteric Akt kinase inhibitors 39, Lindsley and coworkers employed different HTS techniques (Scheme 24) [54]. A polymer-supported base and a fluorous thiol scavenger were used in the alkylation reaction of 40. F-SPE purified intermediate was then used for microwave-assisted cycloaddition of 41. Similar intermediates have been used for generation of an unnatural canthine alkaloid library 42 by performing cycloaddition reactions with an indo-tethered acyl hy-drazide [55]. 

An application of this synthetic strategy by the same group led to the development of a series of potent and selective allosteric Akt (protein kinase B/PKB) kinase inhibitors that induced apoptosis in tumor cells and inhibited Akt phosphorylation in vivo (Scheme 6.261) [451]. 

PI3K/AKT Kinase Pathway Inhibitors in Pre-Clinical Development 366... 

PI3K/AKT KINASE PATHWAY INHIBITORS IN PRE-CLINICAL DEVELOPMENT... 

PC3 Prostate Invasive (EMT) phenotype developed STAT/interferon, P13-kinase, AKT, and integrin signaling PI3-kinase inhibitors blocked invasive cell growth more effectively in 3-D (30)... 

The regulation of translation is accomplished in this system via a specific inhibitory protein and an initiation factor of translation. The binding activity of the inhibitor protein is regulated by protein phosphorylation, and thus, by protein kinases. The activity of protein kinases can be regulated in a multitude of ways. A signal initiating from insulin, for example, can activate the PI3-kinase and the Akt kinase pathway (see 6.6.2), resulting in phosphorylation of 4E-BP1. 

ERK kinase 1 inhibitor, U0126, or a specific p38 kinase inhibitor, SB202190, blocked UVB-induced activation of both Akt and p S6-K. It is worthy to note that UVB-induced p S6-K activation was directly blocked by the addition of EGCG or TF-3, whereas these polyphenols showed only a weak inhibition on UVB-induced Akt activation.5 ... 

Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE, Duggan ME. Allosteric Akt (PKB) kinase inhibitors. Discovery and SAR of isozyme selective inhibitors. Bioorg. Med. Chem Lett. 2005 15 761-765. 

Figure 4.5 Examples of kinase inhibitors, which use diverse binding modes. Further information is in the following references ABFGNF-5 (4.10),18 AKT-Inhibitor VIII (4.11),20 p38-biarylbutyranilide (4.12),21 JNK-docking groove binder (4.13),22 p38-allosteric site (4.14),23 JNK-allosteric site (4.15),23 CHK-allosteric site (4.16),25 JAK-substrate competitive (4.17).27...

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