Filippa N, Sable CL, Hemmings BA, Van Obberghen E. far taken center stage [5C9]. Indeed, less attention has been paid to a direct downstream effector of PI3K, the 3-phosphoinositide-dependent protein kinase 1 (PDK1), whose genetic and pharmacological inhibition is usually supporting its crucial role in cancer progression cIAP1 ligand 2 and metastasis [10]. Unlike PI3K and AKT, only a single PDK1 isoform has been reported in humans. PDK1 is usually a 556-amino-acid made up of enzyme possessing a Pleckstrin Homology (PH) domain name and a catalytic domain name characterized by the typical bi-lobal kinase fold where the ATP co-factor is usually sandwiched between an amino-terminal small lobe and a carboxy terminal larger lobe (Physique 1) [11]. PDK1 is usually constitutively active owing to its auto-phosphorylation at residue Ser241 located at the center of the so called activation loop, which mediates an inter-molecular (IC50 values ranging from 670 nM to 2.5 M. A structurally comparable series of compounds where a thiazole is the central core instead of thiophene (XXIV, Table 2) was patented in 2010 2010 [105]. Herein, Merck claimed 26 compounds, which still showed potent inhibition against JAK2 (IC50 from 10 nM to 1 1 M) and only poor inhibition against PDK1 (IC50 30 M). No data on selectivity has been reported. Similarly, 1-amino-5animal models as recently published [24]. Two recent publications [107C108] reported around the synthesis, PDK1 inhibition and cellular activity of pyrrolopyridinylpyrimidines represented by structures XXVI in Table 2. The HYPB most potent of these series are reported to inhibit PDK1 in a kinase activity assay with IC50 values in the low nanomolar range. potency was confirmed in cellular functional assays where cIAP1 ligand 2 they show to inhibit p-AKT Thr308 in PC-3 cells at fairly low concentrations (10 nM to 20 M). Isosteric replacement of the pyrrolopyridine with the pyrrolopyrazine ring led to the main core structure claimed in a later patent describing pyrrolopyrazinylpyrimidine derivatives (XXVII, Table 2) as new PDK1 inhibitors [109]. The most potent compound of this series (XXVII, Table 2) tested in both PDK1 kinase assay and p-AKT Thr308 cell based assay, exhibited IC50 values of 0.12 M and 0.8 M, respectively. Another patent form Merck discloses the characterization of pyrazolopyridines and imidazopyridines (XXVIII, Table 2) as inhibitors of PDK1 [110]. These compounds, however, inhibited with IC50 values less than 30 M at least one of the following proteins: Fibroblast Growth Factor Receptor 3 (FGFR3), Neurotrophic Tyrosine Kinase Receptor 3 (NTRK3), Ribosomal Protein S6 Kinase (RP-S6K) and Wee1-like protein kinase (WEE1). Apart from the above kinases which are all potential therapeutic targets in cancer, these classes of compounds inhibit also the Microtubule Affinity Regulating Kinase (MARK) and, for this reason, it has been patented their possible use in the treatment of Alzheimers disease as well. Researchers at Merck in 2010 2010 patented heterocyclic carboxamides (XXIX, Table 2) as PDK1 inhibitors [111], tested in both kinase activity (IC50 values less than 30 M) and cell based assays (although no inhibition data are reported), looking at the phosphorylation levels in cIAP1 ligand 2 PC-3 cells of cIAP1 ligand 2 the direct PDK1 substrates RSK (p-Ser221), AKT (p-Thr308) and the downstream effector S6RP (p-Ser235/236). From a chemical point of view, these molecules (XXIX, Table 2), are somewhat related to the previously patented and recently published series from Sunesis Pharmaceuticals and Biogen Idec., Inc. (V, Table 1), discovered by tethering two fragments with a flexible linker [25] [112]. Due to their chemical similarity, it could be speculated a similar binding pose, where the urea moiety is usually hydrogen bonded with the hinge residues Ser160 and Ala162 and the difluorobenzyl cIAP1 ligand 2 ring interacts with hydrophobic residues of the DFG-out pocket; similarly, the heterocyclic keto group could interact with the backbone amide of Asp223 of the DFG motif. The unique allosteric inhibition due to the binding of the inactive (DFG-out) conformation of PDK1 has been extensively studied in cancer cells for the Sunesis lead compound, in a recent paper from the Merck group [26]. Another patent from Merck explains the synthesis of 3-([1,2,3]triazol-4-yl)-pyrrolo[2,3-]pyridine derivatives (XXX, Table 2) as PDK1 inhibitors [113]. Using the copper mediated click chemistry approach.