Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration
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- 作者：John J. Caldwell ; Thomas G. Davies ; Alastair Donald ; Tatiana McHardy ; Martin G. Rowlands ; G. Wynne Aherne ; Lisa K. Hunter ; Kevin Taylor ; Ruth Ruddle ; Florence I. Raynaud ; Marcel Verdonk ; Paul Workman
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：April 10, 2008
- 年：2008
- 卷：51
- 期：7
- 页码：2147 - 2157
- 全文大小：861K
- 年卷期：v.51,no.7(April 10, 2008)
- ISSN：1520-4804
文摘
Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor−PKA−PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3-d]pyrimidine inhibitors of PKBβ with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA−PKB chimera.