Kinase biased library

Trask, O.J., Jr. et al. 2006. Assay development and case history of a 32K-biased library high-content MK2-EGFP translocation screen to identify p38 mitogen-activated protein kinase inhibitors on the Array Scan 3.1 imaging platform. Meth. Enzymol. 414, 419-439. 

Forward Chemical Genomics Using a Kinase-biased Compound Library... 

Schreiber and co-workers recentiy reported (134, 135) the synthesis of two SP pool libraries L3 and L4 based on the structmes of a phage display-derived dodecapeptide ligand of the SH3 domain of the tyrosine kinase Src (7.14, Fig. 7.13) (136), of its truncated version (7.15), and of a nonpeptide ligand derived from an encoded primary library (7.16, Fig. 7.13) (137). The authors kept the common motif proline-leucine-proline (PEP) in the biased library structmes and explored the left (library L3, 2500 members. Fig. 7.13) and the right part of the ligand sequences (library L4, 125,000... 

A third revelation was that there were some common problems, for example, the toxicity of lead compounds against kinase targets or the need to develop biased libraries of compounds to enhance hit finding or lack of structural information about the specific kinase enzymes. 

Fig. 15.2-15 Development of kinase-biased screening libraries during an NMR-based fragment approach. The K, values of the fragments are obtained by quantification of the STD NMR resonances of an adenosine derivative, which is used as the reporter ligand in a competition assay, (a) As a proof of principle, published high-affinity ligands are fragmented into their components. The NMR method is applied to this validation set, which reveals the typical affinities of a particular kinase toward the standard kinase fragments. For example, fragments usually exhibit higher affinities to kinase A...

A compromise between large unbiased and small focused libraries has become popular, especially for pharmaceutical applications. These biased-targeted libraries are not inspired by a precise structural information, but rather by general information regarding similar classes of targets (e.g., kinases or 7-transmembrane receptors) or by the desired activity-unrelated profile that a drug must possess (e.g., the molecular weight, the partition coefficient, the water solubihty, and other physicochemical properties). Their main properties are fisted in Fig. 5.6. 

Biased combinatorial libraries—novel ligands for the Sh3 do- 106. main of phosphatidylinositol 3-kinase. J. Am. Chem. Soc. 1993 115 12591-12592. 

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