NIH Chemical Genomics Center, National Human Genome Research Institute, Bethesda, MD 20892-3370, USA.
Bioorg Med Chem Lett. 2009 Dec 1;19(23):6700-5. doi: 10.1016/j.bmcl.2009.09.121. Epub 2009 Oct 3.
A series of substituted 6-arylquinazolin-4-amines were prepared and analyzed as inhibitors of Clk4. Synthesis, structure-activity relationships and the selectivity of a potent analogue against a panel of 402 kinases are presented. Inhibition of Clk4 by these agents at varied concentrations of assay substrates (ATP and receptor peptide) highly suggests that this chemotype is an ATP competitive inhibitor. Molecular docking provides further evidence that inhibition is the result of binding at the kinase hinge region. Selected compounds represent novel tools capable of potent and selective inhibition of Clk1, Clk4, and Dyrk1A.
一系列取代的 6-芳基喹唑啉-4-胺被制备并分析为 Clk4 的抑制剂。本文介绍了合成、构效关系以及针对 402 种激酶的一个有效类似物的选择性。这些试剂在不同浓度的测定底物（ATP 和受体肽）下对 Clk4 的抑制强烈表明该化学型是一种 ATP 竞争性抑制剂。分子对接进一步提供了抑制是由于结合在激酶铰链区域的证据。选定的化合物代表了能够有效且选择性抑制 Clk1、Clk4 和 Dyrk1A 的新型工具。
