title: Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt.
abstract: Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed.
authors.affiliation: Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA. gui-dong.zhu@abbott.com
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Jianchun
authors.initials: J
authors.lastname: Gong
authors.forename: Viraj B
authors.initials: VB
authors.lastname: Gandhi
authors.forename: Keith
authors.initials: K
authors.lastname: Woods
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Ran
authors.initials: R
authors.lastname: Guan
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Mulugeta
authors.initials: M
authors.lastname: Mamo
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: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D051057:Proto-Oncogene Proteins c-akt; C023666:pyridine