Kinases targeting

Protein Kinases Target Recognition and Intrasteric Control... 

Recently, structure-guided approaches have been used much more frequently at the hit-finding stage of drug discovery and, as this review seeks to demonstrate, these approaches have had a major impact on a number of kinase targets. The closer integration of these tools, combined with ongoing... 

More recently attempts to generate highly selective quiescent affinity labels have been made for a number of protease and kinase targets. As examples, inhibitors of the Rhinovirus 3C protease (Mathews et al 1999) and of the epidermal growth factor receptors (Boschelli, 2002), both incorporating Michael acceptors to covalently inactivate cysteine residues in their target enzymes (Lowry and Richardson, 1981 Figure 8.6), have entered human clinical trials for the treatment of rhinovirus infection and cancer, respectively. 

Only three amino acids have a hydroxyl functional group in their side chain tyrosine, serine and threonine. Some kinases target only tyrosine residues (tyrosine kinases) whereas others may phosphorylate serine or threonine (Ser/Thr kinases). An enzyme protein (the substrate for the kinase) may have several tyrosine, serine or threonine residues within its primary sequence, but only some of these are subject to phosphorylation by a particular kinase (see Figure 3.6)... 

In contrast to c-Jun, phosphorylation of the tumor suppressor p53 by CSN-associated kinases targets the protein for degradation by the Ub system [35]. For p53 stability, modification on Thrl55 is most important as shown by mutational analysis [35] and by using different p53 peptides [31]. Mutation of Thrl55 to Val led to stabilization of the transiently expressed p53 mutant in HeLa as well as in HL60 cells [35]. Inhibitors of CSN-associated kinases such as curcumin [18] caused stabilization of cellular p53 followed by massive cell death [35]. 

Stepanova, L., X. Leng, S. B. Parker, and J. W. Harper. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10 1491-502.1996. 

Dudley DT (2004) Cambridge Healthcare International 2nd Annual Protein Kinase Targets Strategies for Drug Development, Boston, MA, 9-10 June 2004... 

PLK-1 is a relatively novel kinase target and a number of naturally occurring, broadly active kinase inhibitors are being considered as starting points for the design of more selective inhibitors of this enzyme. These compounds will be presented first, followed by a summary of the data available for the only clinical candidate reported up to this time, BI-2536 (103), and a survey of the literature on the chemical series now being pursued by the pharmaceutical industry. A recent review of this topic is also available [256]. 

Tiedemann RE, Zhu YX, Schmidt J et al (2010) Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6. Blood 115 1594-1604... 

Xi, H., Lunney, E. A. (2010) The design, annotation and application of a kinase-targeted-library, in (Zhou, J. Z. ed.) Chemical Library Design. Humana Press, New York, Chapter 14. 

The Design, Annotation, and Application of a Kinase-Targeted Library... 

Key words Protein kinase, kinase-targeted library, library design, kinase chemical cores, substructure search, SMARTS Query, subsetting, binding mode annotation. 

Kinase protein/ligand crystal complexes were retrieved from the Pfizer Crystal Structure Database, an in-house X-ray structure repository that contains internally solved structures and selected ones imported from the Protein Data Bank (1). Kinase assay data were obtained by querying against Pfizer screening database for screens associated with any kinase target and tagged with IC50 or ICi as the endpoint type. 

Lowrie, J. F., Delisle, R. K., Hobbs, D. W., Diller, D. J. (2004) The different strategies for designing GPCR and kinase targeted libraries. Comb Chem High Throughput Screen 7, 495-510. 

Chapter 14 in Section IV describes a workflow for designing a kinase targeted library. It illustrates how to assemble a lead generation library for a target family using known ligand-target family interaction data from various sources. 

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