Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany.
J Med Chem. 2011 Oct 13;54(19):6714-23. doi: 10.1021/jm2005892. Epub 2011 Sep 14.
Protein kinase inhibitors with an allosteric mode of action are expected to reach, in many cases, higher selectivity for the target enzyme than ATP-competitive compounds. Therefore, basic research is aiming at identifying and establishing novel sites on the catalytic domain of protein kinases which might be targeted by allosteric inhibitors. We previously published the first structure-activity relationships (SARs) for allosteric activators of protein kinase PDK1. Here, we present the design, synthesis, and SAR data on a series of novel compounds, 4-benzimidazolyl-3-phenylbutanoic acids, that inhibit the atypical protein kinace C (PKC) ζ via binding to the PIF-pocket. Key positions were identified in the compounds that can be modified to increase potency and selectivity. Some congeners showed a high selectivity toward PKCζ, lacking inhibition of the most closely related isoform, PKCι, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKCζ without loss of potency compared to the cell-free assay.
蛋白激酶抑制剂的变构作用模式预计将在许多情况下比 ATP 竞争性化合物对靶酶具有更高的选择性。因此，基础研究旨在确定和建立蛋白激酶催化结构域上可能成为变构抑制剂靶点的新位点。我们之前发表了蛋白激酶 PDK1 的第一个变构激活剂的结构-活性关系 (SAR)。在这里，我们介绍了一系列新型化合物 4-苯并咪唑基-3-苯基丁酸的设计、合成和 SAR 数据，这些化合物通过结合 PIF 口袋抑制非典型蛋白激酶 C (PKC) ζ。确定了化合物中的关键位置，可以对其进行修饰以提高效力和选择性。一些同系物对 PKCζ 具有高选择性，对最密切相关的同工型 PKCι 和其他 AGC 激酶没有抑制作用。此外，有证据表明，与无细胞测定相比，这些化合物在细胞内对 PKCζ 也具有活性，而效力没有降低。
