Kinase inhibition

Imidazo[l,5-a]quinoxalines 178-180, containing an arylamine moiety in the 4-position, are inhibitors of the Src-family kinases p56Lck the 50 % inhibition concentrations (IC50) of these compounds are 170.2, 2.0 and 1.7 nmol L, respectively (Chen et al. 2002a, b, c). The presence of an amide group in the 8-position, along with the 4-arylamine substituent, confers to compound 181 the ability to irreversibly inhibit Bmton s tyrosine kinase (BTK) (IC50 = 1.93 nmol L ) (Kim et al. 2011). This compound is used in the treatment of rheumatoid arthritis. 

Among imidazo[l,2-a]quinoxalines, there are a highly efiBcient IkB-kinase inhibitor-compound 182 (BMS-345541) (Burke et al. 2003)-and a selective inhibitor of JNKl kinase-compound 183 (AX-13587) (Li et al. 2013). 

One of the important new areas of biological studies of imidazo[l,5-fl]- and imidazo[l,2-a]quinoxaline derivatives focuses on their antitumour activity. New potent dual CK2 and PIM kinase inhibitors with the antiproliferative activity against cancer cells have been described (Pierre et al. 2012), for example, compound 184 (IC50 = 0.038 (PIMl), 0.043 (P1M2), 0.035 (CK2) mol L ). 

Currently, study of the effect of the tricyclic compounds under consideration on the central nervous system is continued. 4-Alkylamino-l-hydroxymethylimidazo[l,2-a]quinoxalines 188 are Aj adenosine receptor antagonists, the compound with = Cl, is pyrrolidin-l-yl exhibiting the highest activity [inhibition constant (fi), 7 nmol L ] (Liu et al. 2004). It has been stated that the hydroxymethyl group in the 1-position displays the potent affinity toward the binding site of the receptor (Liu et al. 2004). 

Imidazo[l,2-fl]- and imidazo[l,5-a]quinoxaIines have been studied as histamine receptor inhibitors (Borchardt et al. 2011a, b). 

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EGFR Receptor tyrosine kinase Inhibition of cell proliferation and colony formation decrease of in vivo tumorigenicity... 

RET Receptor tyrosine kinase Inhibition of colony formation... 

Franci C, Gosling J, Tsou CL, Coughlin SR, Charo IF (1996) Phosphorylation by a G protein-coupled kinase inhibits signaling and promotes internalization of the monocyte chemoattractant protein-1 receptor. Critical role of carboxyl-tail serines/threonines in receptor function. J Immunol 157 5606-5612... 

GAO Y H and YAMAGUCHI M (2000) Suppressive effect of genistein on rat bone osteoclasts Involvement of protein kinase inhibition and protein tyrosine phosphatase activation. Int J Mol Med 5, 261-7. 

Experimental screening established that compound 42 shown in Fig. 8.11 disrupts ZipA-FtsZ protein-protein interaction. However, previous studies suggested potential issues with toxicity associated with this class of compounds. Additionally such amine-substituted pyridyl-pyrimidines are heavily patented in the context of kinase inhibition. Both of these factors limit the scope of the subsequent lead optimization process, to transform this compound into a viable drug. Knowledge that compound 42 was a micromolar inhibitor of ZipA-FtsZ was exploited by searching for molecules that were similar in shape. 

Included in this table are criteria related to kinase inhibition, including detailed analyses of reversibility, detergent effects, and competition with ATP. Also listed are criteria for selectivity, cellular activity, and the physicochemical and in vitro ADME profiles. The final two criteria require the lead to be part of a series of compounds with demonstrated SAR. 

McGowan, C. H., and Russell, P. (1993). Human weel kinase inhibits cell division by phosphorylating p34cdc2 exclusively on tyrl5. EMBO J. 12 75-85. 

Nasmyth If you reactivated the kinase, given that the kinase inhibits prereplication complex formation, this would do the job. There are two ways of preventing replication one is not to make the components of the pre-replication complex, the other is to keep the kinase high, which inhibits that formation. This could be an explanation of the Nenopus work. 

D. indicus Gaertn. is known to abound with anthraquinones, but its pharmacological potential remains unexplored to date (20,21). Note that damnacanthal is a common component of the Damnacanthus species. Faltynek et al. made the interesting observation that damnacanthal inhibits the enzymatic activity of tyrosine kinase, which is involved in the propagation of metastases (22). An interesting development from this observation would be to assess the topoisomerase inhibitory activity of the Damnacan-thus species, an activity that could be associated with tyrosine kinase inhibition, hence enormous chemotherapeutic potentials. 

Schaffhauser, H., Cai, Z., Hubalek, F., Macek, T. A., Pohl, J., Murphy, T. J., and Conn, P. J. (2000) cAMP-dependent protein kinase inhibits mGluR2 coupling to G proteins by direct receptor phosphorylation. J. Neurosci. 20, 5663-5670. 

Histamine Hj receptor HIstamlnergic neurons, eosinophils, DC, monocytes Low expression in peripheral tissues Enhanced Ca +, MAP kinase, inhibition of cAMP ... 

Figure 2.4 Key acyl hydrazone DCL components for kinase inhibition.

Rohitukine (112) Flavone Alvocidib (flavopiridol, HMR 1275) (113) Oncology Cyclin-dependent kinase inhibition Phase III (NSCLC) Phase Ilb (CLL) Sanofi-Aventis 700-702... 

Genistein (116) Isoflavone Genistein (116) Oncology (antitumor) Protein-tyrosine kinase inhibition, antioxidative Phase I/II Astellas, Bausch Lomb 708... 

There was a time not long ago when researchers were united in the behef that potent, selective kinase inhibition was crucial for the development of safe drugs and that it would be very difficult, if not impossible, to achieve. Conventional wisdom held that the high concentration of cytosoHc ATP (in the milHmolar range) precluded the identification of nanomolar ATP-competitive kinase inhibitors in cell-based assays. Some of these beliefs were grounded... 

The patent literature has reports of many compounds that are claimed to have Aurora kinase inhibition activity but in some of these cases it is not possible to determine whether these compounds are pan-kinase inhibitors or if the compounds are selective for the Aurora kinases. We Umited this review to publications that give specific data for the Aurora kinases and have pertinent selectivity data. Another review has appeared recently [171]. 

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