Multiple kinases

There is evidence that multiple kinases can phosphorylate several GABAa receptor subunits, to alter GABAergic activity in the brain (Browning et al. 1993 Poisbeau et al. 1999). Depending on the brain area and /or the receptor subunits involved, phosphorylation by kinases can result in either activation or inhibition... 

Although the above methodologies proved to be very successful in identifying active kinase inhibitors, they utilized "generic" kinase models and did not address selectivity issues. An interesting recent report has attempted to create quantitative structure-activity relationship (QSAR) models based on data sets of compounds tested against multiple kinases [33]. 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

Finally, development of drugs targeted toward modification of kinases and phosphatases required for activation or inhibition of particular transcription factors is a promising therapeutic approach. The problem with this paradigm is the specificity of the kinases and phosphatases, since they will often act enzymatically on multiple proteins (see Chs 24 and 25). Furthermore, such drugs often lack specificity and may interact with multiple kinases or phosphatases. 

Sorafenib is a reversible ATP-competitive inhibitor of multiple kinases developed by Bayer and Onyx. It was originally described as a C-Raf inhibitor, but has since been reported to inhibit B-Raf, p38a, KDR, and a several other... 

Hu, Y., Swerdlow, S., Duffy, T. M., Wein-mann, R., Lee, F. Y. and Li, S. (2006) Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci USA 103, 16870-16875. 

Thulasiraman Y, Wang Z, Katrekar A, Lomas L, Yip TT. Simultaneous monitoring of multiple kinase activities by SELDI-TOF mass spectrometry. Methods Mol Biol 2004 278 205-214. 

As demonstrated by these marketed anticancer drugs, ATP competitive inhibitors are generally not as selective as people had thought however, inhibition of multiple kinases appears to be manageable and potentially an advantage when applied to the treatment of cancer. 

G. DMLs that Inhibit Multiple Kinases for Treating Cancer... 

FIGURE 27.11 DMLs that inhibit multiple kinases for treating cancer. 

Understanding the affinity of new inhibitors across multiple kinases will be important to exploring the therapeutic value and liability of the unexplored kinase targets. The next section of this review will focus on the commercial assays available to assess broad kinase inhibitor potency. These assays are currently expanding the breadth of the kinase world and in the future will enable production of inhibitors for most of the kinases on the kinome. 

The KINOMEscan selectivity scores for a selection of the marketed kinase inhibitors demonstrate the potential for the type II inhibitors imatinib 7, sorafenib 8 and lapatinib 10 to display higher selectivity than the type I inhibitors sunitinib 3 and dasatinib 4, especially when only higher affinity off-target interactions are considered (S(100 nM) scores). It can also be seen that, despite their potential to inhibit multiple kinase family members, it is possible to achieve good levels of selectivity with type I inhibitors ([Pg.83]

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