title: Diverse heterocyclic scaffolds as allosteric inhibitors of AKT.
abstract: Wide-ranging exploration of potential replacements for a quinoline-based inhibitor of activation of AKT kinase led to number of alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, and one such compound demonstrated pharmacodynamic knockdown of phosphorylation of AKT and downstream biomarkers in vivo and inhibition of tumor growth in a breast cancer xenograft model.
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom. jason.kettle@astrazeneca.com
authors.forename: Jason G
authors.initials: JG
authors.lastname: Kettle
authors.forename: Simon
authors.initials: S
authors.lastname: Brown
authors.forename: Claire
authors.initials: C
authors.lastname: Crafter
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.forename: Phillippa
authors.initials: P
authors.lastname: Dudley
authors.forename: Gary
authors.initials: G
authors.lastname: Fairley
authors.forename: Paul
authors.initials: P
authors.lastname: Faulder
authors.forename: Shaun
authors.initials: S
authors.lastname: Fillery
authors.forename: Hannah
authors.initials: H
authors.lastname: Greenwood
authors.forename: Janet
authors.initials: J
authors.lastname: Hawkins
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.forename: Keith
authors.initials: K
authors.lastname: Johnson
authors.forename: Clare D
authors.initials: CD
authors.lastname: Lane
authors.forename: Martin
authors.initials: M
authors.lastname: Pass
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Pink
authors.forename: Helen
authors.initials: H
authors.lastname: Plant
authors.forename: Sabina C
authors.initials: SC
authors.lastname: Cosulich
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001682:Biological Availability; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D015415:Biomarkers; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; C548887:MK 2206; D011719:Pyrazines; D011720:Pyrazoles; D011724:Pyridazines; D011725:Pyridines; D011799:Quinazolines; D051057:Proto-Oncogene Proteins c-akt