Kinase Targets (kinase + target)

Distribution by Scientific Domains

Selected Abstracts

Synthesis and pp60c-Src Tyrosine Kinase Inhibitory Activities of Novel Indole-3-Imine and Amine Derivatives Substituted at N1 and C5

Zuhal Kiliç
Abstract A series of novel 1,3,5-trisubstituted indole derivatives, namely, N -benzyl 5-phenyl indole-3-imine, N -benzyl-5-(p -fluorophenyl)indole-3-imine and their corresponding amine congeners, were designed and synthesized as pp60c-Src tyrosine kinase inhibitors, and their inhibitory activities toward pp60c-Src tyrosine kinase were evaluated by in-vitro kinase assay. Pre-screening at two doses of compounds against kinase target revealed that, except for the N -benzyl-5-phenyl indole imine derivatives 7a,7d, all indole derivatives show the target inhibition at varying levels. Consequently, the compounds, 8c, 8f, 8g, and 8h, were selected for prescreening tests. The dose-response curves for up to six concentrations (250 to 7.8 ,M) of the active compounds were obtained by tyrosine kinase assay and the four-parameter logistic analysis of these data resulted in the IC50s of 4.69, 74.79, 75.06, and 84.23 ,M for compounds 8c, 8f, 8g, and 8h, respectively. Therefore, compound 8c, 1-(1-benzyl-5-phenyl-1H -indole-3-yl)- N -(4-fluorobenzyl)methanamine·HCl, was the promising inhibitor for pp60c-Src, followed by compounds 8g and 8h. Under the same conditions, compound 8f did not provide any reasonable inhibition pattern to be considered as active compound. Therefore, among all four active compounds, compound 8f was not found suitable for further analysis. [source]

Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets,

Justine Y.Q. Lai
Abstract This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an ,in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection. © 2004 Wiley Periodicals, Inc. [source]

Functional Classification of Protein Kinase Binding Sites Using Cavbase

CHEMMEDCHEM, Issue 10 2007
Daniel Kuhn Dr.
Abstract Increasingly, drug-discovery processes focus on complete gene families. Tools for analyzing similarities and differences across protein families are important for the understanding of key functional features of proteins. Herein we present a method for classifying protein families on the basis of the properties of their active sites. We have developed Cavbase, a method for describing and comparing protein binding pockets, and show its application to the functional classification of the binding pockets of the protein family of protein kinases. A diverse set of kinase cavities is mutually compared and analyzed in terms of recurring functional recognition patterns in the active sites. We are able to propose a relevant classification based on the binding motifs in the active sites. The obtained classification provides a novel perspective on functional properties across protein space. The classification of the MAP and the c-Abl kinases is analyzed in detail, showing a clear separation of the respective kinase subfamilies. Remarkable cross-relations among protein kinases are detected, in contrast to sequence-based classifications, which are not able to detect these relations. Furthermore, our classification is able to highlight features important in the optimization of protein kinase inhibitors. Using small-molecule inhibition data we could rationalize cross-reactivities between unrelated kinases which become apparent in the structural comparison of their binding sites. This procedure helps in the identification of other possible kinase targets that behave similarly in "binding pocket space" to the kinase under consideration. [source]

Are MAP Kinases Drug Targets?

CHEMMEDCHEM, Issue 8 2007
but Difficult Ones
Abstract Pharmaceutical companies are facing an increasing interest in new target identification and validation. In particular, extensive efforts are being made in the field of protein kinase inhibitors research and development, and the past ten years of effort in this field have altered our perception of the potential of kinases as drug targets. Therefore, in the drug discovery process, the selection of relevant, susceptible protein kinase targets combined with searches for leads and candidates have become a crucial approach. The success of recent launches of protein kinase inhibitors (Gleevec, Imatinib, Sutent, Iressa, Nexavar, Sprycel) gave another push to this field. Numerous other kinase inhibitors are currently undergoing clinical trials or clinical development. Some questions are nevertheless unanswered, mostly related to the great number of known kinases in the human genome, to their similarity with each other, to the existence of functionally redundant kinases for specific pathways, and also because the connection between particular pathways and diseases is not always clear. The review is leading the reader through a panoramic view of protein kinase inhibition with a major focus on MAPK, successful examples and clinical candidates. [source]