Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration

Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitoi-PKA-PKB chimera complexes efficiently guided improvements ill the potency and selectivity of: the compounds, resulting in the identification of nanomolar 6-(piperidin-l-yl)purine, 4-(piperidin-l-yl)-7-azaindole, and 4-(piperidin-l-yl)pyrrolo[2,3-d]pyrirnidine inhibitors of PKB beta with antiproliferative activity and showing pathway inhibition ill 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.