Beyond kinase inhibitors

While this version of the KTL successfully captured known kinase inhibitor series, the goal for our next-generation KTL would be to apply de novo design methods to incorporate novel chemotypes and to incorporate more nonclassical chemotypes that bind to a protein kinase beyond the typical ATP pocket. 

Tecle, H., Shao, J., Li, Y., et al. (2009) Beyond the MEK-pocket Can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs Does the MEK-pocket exist in kinases other than MEK Bioorg. Med. Chem. Lett. 19, 226-9. 

The involvement of protein kinase C in the enhancement of malignant cell transformation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin was studied by W6LFLE and Marquardt (1996). The protein kinase inhibitor H-7 markedly reduced the in vitro promoting activity of 12-0-tetradecanoylphorbol-13-acetate but did not affect the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin. In accord with these results, 12-0-tetradecanoylphorbol-13-acetate, but not 2,3,7,8-tetrachlorodibenzo-p-dioxin, enhanced the protein kinase C activity in C3H/M2 fibroblasts. Since 12-0-tetradecanoylphorbol-13-acetate-mediated activation of protein kinase C was not affected by ascorbic acid plus a-tocopherol, that the antioxidants interfere with tumour promotion at a step beyond protein kinase C activation. 

After these general comments let us further test the idea of thermodynamic buffering on an experimental basis by repeating the above experiment but this time in the presence of an inhibitor of adenylate kinase, namely, diadenosine pentaphosphate. As is depicted in Fig. 6b the buffering effect of the adenylate kinase is abolished by inhibiting this enzyme and it becomes now possible to drive the system beyond the state of optimal efficiency by increasing the hexokinase concentration in the medium. Note that it was not possible to measure points closer to level flow than the ones shown in the figure. This is due to technical reasons. At the lowest phosphate potentials the ATP/ADP ratios where of the order... 

Mood disorders characterized by elevations of mood above normal as well as depressions below normal are classically treated with lithium, an ion whose mechanism of action is not certain. Candidates for its mechanism of action are sites beyond the receptor in the second messenger system, perhaps either as an inhibitor of an enzyme, called inositol monophosphatase, involved in the phosphatidyl inositol system as a modulator of G proteins, or even as a regulator of gene expression by modulating protein kinase C (Fig. 7—22). 

The lipophilic environment created by residues that form the adenine-binding pocket extends sufficiently beyond the opening of the pocket to create an additional lipophilic binding area in front of the adenine. This pocket may not be accessible to inhibitors that bind into tightly closed adenine pockets. Inhibitor accessibility to this pocket may also be restricted for some kinase families. For example, the AGC family kinases (PKA, PKC, AKT) have a C-terminal tail that extends back into N-terminal domain and caps the adenine site with a phenylalanine (see Section 2.2.3.3). Inhibitor-kinase structures that bind an aryl ring in this site include 10 in CDK2 (Fig. 2.5 B) [67], 9 in CDK2 [66], and 17 (Scheme 2.4) in p38... 

In this review we focus on the discussion of those small molecules which are described not only to inhibit GSK-3P in a primary kinase assay, but also where there is pubhshed data on how the compounds influence the level of tau phosphorylation in either a cellular or in vivo system (see [55] for a broader review). This latter criterion narrows down the compounds for discussion considerably, to only nine distinct chemical sub-types, where two such series from AstraZeneca—3-aminopyrazinyl-2-carboxamides and oxindolequinazohnes—are reported for the first time. In addition to these there are two other inhibitor classes described in the hterature which will not be discussed in the course of this review sodium valproate [51], where there is conflicting data [52], and large molecules such as GSK-3 binding proteins (e.g. amongst others GSKIP or FRAT-1 [50,53]), which are beyond the scope of this focus on small molecules. 

Genistein has been used for years as a model inhibitor of protein tyrosine kinases (PTKs). This ubiquitous enzyme, which is also present in thyroid foUicular ceUs, is involved in phosphorylation of tyrosyl residues of membrane-bound receptors leading to signal transduction. One of the signal transduction cascades leads to topoisomerase II, which participates in DNA replication. Blocking PTK activity is one of the mechanisms believed to be responsible for the anticancer potential of genistein. For reviews addressing this issue, which are beyond the scope of this chapter, see Peterson (1995), and Ravindranath et al (2004). 

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