title: Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma.
abstract: The phosphoinositide-dependent kinase-1 (PDK1) is one of the main components of the PI3K/Akt pathway. Also named the "master kinase" of the AGC family, PDK1 plays a critical role in tumorigenesis, by enhancing cell proliferation and inhibiting apoptosis, as well as in cell invasion and metastasis formation. Although there have been done huge efforts in discovering specific compounds targeting PDK1, nowadays no PDK1 inhibitor has yet entered the clinic. With the aim to pick out novel and potent PDK1 inhibitors, herein we report the design and synthesis of a new class of molecules obtained by merging the 2-oxo-indole nucleus with the 2-oxo-pyridonyl fragment, two moieties with high affinity for the PDK1 hinge region and its DFG-out binding site, respectively. To this purpose, a small series of compounds were synthesised and a tandem application of docking and Molecular Dynamic (MD) was employed to get insight into their mode of binding. The OXID-pyridonyl hybrid 8, possessing the lower IC50 (IC50 = 112 nM), was also tested against recombinant kinases involved in the PI3K/PDK1/Akt pathway and was subjected to vitro studies to evaluate the cytotoxicity and the inhibition of tumour cell migration. All together the results let us to consider 8, as a lead compound of a new generation of PDK1 inhibitors and encourage us to further studies in this direction.
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Sestito
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Nesi
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Zappelli
authors.affiliation: Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56126 Pisa, Italy; Istituto Nazionale di Fisica Nucleare (INFN), Largo Bruno Pontecorvo 3, 56127 Pisa, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Di Maio
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Annalina
authors.initials: A
authors.lastname: Lapucci
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy. Electronic address: simona.rapposelli@farm.unipi.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D064413:3-Phosphoinositide-Dependent Protein Kinases
keywords: GBM stem cells; Glioblastoma; Kinase inhibitors; Oxindole derivatives; PDK1 inhibitors; Pyridonyl derivatives