Structure-based design of PDK1 inhibitors Anders Poulsen ⇑ , Stéphanie Blanchard, Chang Kai Soh, Chaiping Lee, Meredith Williams, Haishan Wang, Brian Dymock S/BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore article info Article history: Received 5 October 2011 Revised 26 October 2011 Accepted 2 November 2011 Available online 9 November 2011 Keywords: 3-Phosphoinositide-dependent kinase 1 (PDK1) Structure-based design Selectivity Inhibitor 4-Aryl-purine abstract A macrocyclic 2-anilino-4-phenyl-pyrimidine CDK/Flt3/JAK2 inhibitor was found to have moderate PDK1 activity. After docking into a PDK1 X-ray structure it was suggested that the pyrimidine ring could be substituted for a purine thereby increasing the number of hydrophobic contacts with the protein and forming an additional hydrogen bond to the kinase hinge. Deletion of the macrocyclic linker allowed a more rapid optimisation of the aromatic substituents as well as the introduction of an amino-amide sol- ubility tag. This improved both binding to the enzyme and physiochemical properties without compro- mising ligand efficiency. Ó 2011 Elsevier Ltd. All rights reserved. 3-Phosphoinositide dependent protein kinase-1 (PDK1) is part of the Akt/PKB pathway which regulates many growth factors and oncogenes. PDK1 signals to a number of proteins shown to be important in cancer, for example, S6K and AKT. PDK1 is reported to phosphorylate Akt on residue Thr308 thereby resulting in it’s activation. Catalytically active Akt promotes cancer progression through suppression of apoptosis and stimulation of proliferation, metabolism and angiogenesis. 1 Consequently PDK1 inhibitors may be promising oncology drugs and several medicinal chemistry ef- forts aimed at generating potent PDK1 inhibitors have recently been published. 2 Kinase inhibitors from our in-house collection were screened for activity against PDK1. Compound 1 (Fig. 1) and derivatives pos- sessing a macrocyclic 2-aniline-4-phenyl-pyrimidine scaffold were found to be moderately active (see Table 1). 3 These scaffolds are low molecular weight (350–400 Dalton) and generally display good ADME properties. 5 Consequently compounds in this series were considered good leads for a PDK1 project. Here we report the design of a new PDK1-inhibitor chemotype by structure-guided modification of the lead compound 1. Figure 2 displays compound 1 docked into PDK1. 6 Two hydro- gen bonds are formed to Ala162 of the kinase hinge. 7 In the figure the torsion angle between the beta and gamma carbon of Glu166 has been rotated by 120° compared to the angle seen in the X- ray structure thereby forming a salt bridge to the basic nitrogen in the macrocyclic linker 1 as well as a hydrogen bond to the back- bone NH of Glu166 (not shown). This is a common conformation of glutamate observed in many protein structures. The area in front of the gatekeeper (Leu159) and the backbone oxygen of Leu159 is not occupied by the ligand. Figure 3 displays 1 with the co-crystallized ligands ATP and compound 5 superimposed on the binding site. With its bromine substituent, it is apparent that 5 is better able to fill out the binding site in front of the gatekeeper residue. It was noted that the NH 2 in 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.11.006 ⇑ Corresponding author. Tel.: +65 6827 5000; fax: +65 6827 5005. E-mail address: anders@colours.dk (A. Poulsen). Figure 1. Chemical structures of the screening hit, compound 1 and designed compounds 2–4. Compound 5 is an inhibitor published with the PDK1 X-ray structure 1Z5M. 2d Bioorganic & Medicinal Chemistry Letters 22 (2012) 305–307 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl