Design and combinatorial synthesis of a novel kinase-focused library using click chemistry-based fragment assembly.

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Irie T, Fujii I, Sawa M

Design and combinatorial synthesis of a novel kinase-focused library using click chemistry-based fragment assembly.

Bioorg Med Chem Lett. 2012 Jan 1;22(1):591-6. doi: 10.1016/j.bmcl.2011.10.076. Epub 2011 Oct 30.

PubMed ID

22104147 [ View in PubMed

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Abstract

Fragment-based lead discovery is a new approach for lead generation that has emerged in the past decade. Because the initial fragments identified in the fragment screening typically show weak binding affinity, an intensive medicinal chemistry effort would be required to grow initial fragments into a potential lead compound. Here we demonstrate a kinase focused evolved fragment (KFEF) library, constructed by click chemistry-based fragment assembly, that is a valuable source of kinase inhibitors. This combinatorial assembly of two fragments, kinase-privileged alkyne fragments and diversified azide fragments, by two cycloaddition reactions shows a unique potential for the one-step synthesis of structurally diverse evolved fragments. The screening of this triazole-based KFEF library allowed the rapid identification of potent lead candidates for FLT3 and GSK3beta kinase.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Staurosporine	Glycogen synthase kinase-3 beta	IC 50 (nM)	11	N/A	N/A	Details