title: Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors.
abstract: Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
authors.affiliation: Oncology Research, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States. jesus.r.medina@gsk.com
authors.forename: Jesús R
authors.initials: JR
authors.lastname: Medina
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Becker
authors.forename: Charles W
authors.initials: CW
authors.lastname: Blackledge
authors.forename: Celine
authors.initials: C
authors.lastname: Duquenne
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Feng
authors.forename: Seth W
authors.initials: SW
authors.lastname: Grant
authors.forename: Dirk
authors.initials: D
authors.lastname: Heerding
authors.forename: William H
authors.initials: WH
authors.lastname: Li
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Romeril
authors.forename: Daryl
authors.initials: D
authors.lastname: Scherzer
authors.forename: Arthur
authors.initials: A
authors.lastname: Shu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bobko
authors.forename: Antony R
authors.initials: AR
authors.lastname: Chadderton
authors.forename: Melissa
authors.initials: M
authors.lastname: Dumble
authors.forename: Christine M
authors.initials: CM
authors.lastname: Gardiner
authors.forename: Seth
authors.initials: S
authors.lastname: Gilbert
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
authors.forename: Valery
authors.initials: V
authors.lastname: Sudakin
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: Pat G
authors.initials: PG
authors.lastname: Brady
authors.forename: Nino
authors.initials: N
authors.lastname: Campobasso
authors.forename: Paris
authors.initials: P
authors.lastname: Ward
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Axten
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D009025:Morpholines; C000631433:Pdk1 protein, mouse; D010880:Piperidines; D011743:Pyrimidines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases