4-Benzimidazolyl-3-Phenylbutanoic Acids As Novel Pif-Pocket-Targeting Allosteric Inhibitors of Protein Kinase PKC味

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• 作者：Wolfgang Fr枚hner ; Laura A. Lopez-Garcia ; Sonja Neimanis ; Nadja Weber ; Jeanette Navratil ; Frauke Maurer ; Adriana Stroba ; Hua Zhang ; Ricardo M. Biondi ; Matthias Engel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6714-6723
• 全文大小：986K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

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鈥揳ctivity 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) 味 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 PKC味, lacking inhibition of the most closely related isoform, PKC喂, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKC味 without loss of potency compared to the cell-free assay.