title: 2-anilino-4-aryl-8H-purine derivatives as inhibitors of PDK1.
abstract: A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a serine-threonine kinase thought to play a role in the PI3K/Akt signaling pathway, a key mediator of cancer cell growth, survival and tumorigenesis. The synthesis, SAR and ADME properties of this series of compounds are discussed culminating in the discovery of compound 6 which possessed sub-micromolar cell proliferation activity and 65% oral bioavailability in mice.
authors.affiliation: S*BIO Pte. Ltd, The Capricorn, Singapore Science Park II, Singapore, Singapore. stephanie_blanchard@sbio.com
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Blanchard
authors.forename: Chang Kai
authors.initials: CK
authors.lastname: Soh
authors.forename: Chai Ping
authors.initials: CP
authors.lastname: Lee
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Zahid
authors.initials: Z
authors.lastname: Bonday
authors.forename: Kay Lin
authors.initials: KL
authors.lastname: Goh
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Miah Kiat
authors.initials: MK
authors.lastname: Goh
authors.forename: Mohammed Khalid
authors.initials: MK
authors.lastname: Pasha
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility
chemical_list: D000814:Aniline Compounds; D004791:Enzyme Inhibitors; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D011687:Purines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D054852:Small Molecule Libraries; D017346:Protein Serine-Threonine Kinases; C023650:aniline; C030985:purine