Kinase Inhibition Principles

The first section describes the structure of kinases in general, the specific domains as well as the activation mechanism, and is followed by a section on the different kinase inhibition principles. In the next section, a detailed description of the structural features of all kinase inhibitors currently cocrystallized with their target kinase is given. Finally, some structural features that determine the selectivity of several kinase inhibitors are addressed. 

Irreversible inhibitors have a major advantage over their reversible counterparts in that their action is sustained after systemic clearance. However, the pharmaceutical industry usually does not make use of irreversible inhibition principles, because unspecific binding to proteins other than the target enzyme may lead to considerable toxicity. Since most of the current cancer therapies are unspecific and very toxic, the irreversible kinase inhibition principle may well be applied in this research area, provided that an improved risk/benefit ratio is observed [4e],... 

The MLA is used for the detection of point mutations, structural aberrations and aneugenicity. The principle of the assay is that cells deficient in thymidine kinase (TK) due to the tk+/" or tk/ mutation are resistant to the cytotoxic effects of the pyrimidine analogue trifluoro-thymidine (TFT). TK proficient cells are sensitive to TFT. This influences the cellular metabolism and leads finally to an inhibition of further cell division. Thus mutant cells are able to proliferate in the presence of TFT, whereas normal cells, which contain TK, are not. The major advantage of the assay is its ability to detect a broad range of mutagenic events represented by optimal detection of both large and small colonies. 

Triterpenes are widely distributed in plants, and in many cases are the principles responsible for their anti-inflammatory effects. Many of these compounds are active in different in vivo experimental models such as hind paw edema induced by carrageenan, serotonin and phospholipase A2 ear edema induced by phorbol and daphnane esters, ethylphenylpropiolate, arachidonic acid and capsaicin adjuvant arthritis and experimental models of allergy. Other effects have been studied in vitro, and some triterpenes are active against inflammatory enzymes like 5-lipoxygenase, elastase and phospholipase A2. Others inhibit histamine, collagenase and interleukin release, lipid peroxidation and free radical-mediated processes, metabolism of endogenous corticoids, and complement and protein-kinase activities. 

Hochhaus, A. Lahaye, T. Kreil, S. Berger, U. Metzgeroth, G. Hehlmann, R. Selective inhibition of tyrosine kinases - a new therapeutic principle in oncology. Onkologie, 24, 65-71 (2001)... 

Piceatannol, an antileukemic principle known to inhibit proteine-tyrosine kinase (PTK) was chosen as a lead compound for SAR analysis. The fully symmetrical 5-hydroxy isomer was found to be four times more potent than piceatannol. When compared with the reference monomer A46, the fcw-tyrphostin was found to be 150 times more potent in protein tyrosine kinase... 

The active principle of both TAS-102 and FTC-092 with anti-cancer effect is Trifluridine (7). As in the case of Fluorouracil, one of the mechanisms by which compound 7 exhibits its antitumor activity is inhibition of thymidylate synthase [100], More precisely, Trifluridine is transformed into a,a,a-trifluorothymidine monophosphate (76) by thymidine kinase (Scheme 21) similarly to the Fluorouracil derivatives discussed in the previous sections, compound 76 is true inhibitor of thymidylate synthase. However, compound 7 exhibits an anticaneer effect on colorectal cancer cells that have acquired Fluorouracil resistance as a result of the overexpression of thymidylate synthase. 

As it was mentioned in the previous sections, the active principle of Fostamatinib disodium (88) is Tamatinib (92), which is formed by enzymatic hydrolysis of 88 in the intestine. As in the case of lymphoma, the effect of 88 in autoimmune diseases is related to inhibition of Spleen tyrosine kinase (Syk) by 92 [241, 242]. As Syk has the central role in transmission of activating signals within B cells, inhibition of this enzyme lowers expression of a number of pro-inflammatory cytokines and hence leads to immunosuppression [243], Fostamatinib has shown significant efficacy in the treatment of patients with rheumatoid arthritis not responding to Methotrexate (272) (a drug which is used conventionally in therapy), although a number of adverse events were observed [244], If these results are confirmed once Phase III studies are completed, it may hnd a place in the treatment of patients with rheumatoid arthritis with poor response to conventional therapy (Fig. 11). 

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