title: Discovery and SAR of oxindole-pyridine-based protein kinase B/Akt inhibitors for treating cancers.
abstract: We describe a series of potent and selective oxindole-pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC(50) of 0.17nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (11k) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity.
authors.affiliation: Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. gui-dong.zhu@abbott.com
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Viraj B
authors.initials: VB
authors.lastname: Gandhi
authors.forename: Jianchun
authors.initials: J
authors.lastname: Gong
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Ran
authors.initials: R
authors.lastname: Guan
authors.forename: Shayna R
authors.initials: SR
authors.lastname: Magnone
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Alexander
authors.initials: A
authors.lastname: Shoemaker
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.forename: Ken
authors.initials: K
authors.lastname: Jarvis
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: Ron De
authors.initials: RD
authors.lastname: Jong
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C022960:2-oxindole; D051057:Proto-Oncogene Proteins c-akt