title: Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers.
abstract: Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kβ and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Electronic address: bernard.barlaam2@astrazeneca.com.
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Delouvrié
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ellston
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Martina
authors.initials: M
authors.lastname: Fitzek
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Germain
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Urs
authors.initials: U
authors.lastname: Hancox
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Harris
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hudson
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lambert-van der Brempt
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Honorine
authors.initials: H
authors.lastname: Lebraud
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Magnien
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Maryannick
authors.initials: M
authors.lastname: Lamorlette
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Le Griffon
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Morgentin
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Ouvry
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Ken
authors.initials: K
authors.lastname: Page
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Pasquet
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Urszula
authors.initials: U
authors.lastname: Polanska
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Linette
authors.initials: L
authors.lastname: Ruston
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Twana
authors.initials: T
authors.lastname: Saleh
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vautier
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Lara
authors.initials: L
authors.lastname: Ward
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004285:Dogs; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: C000609108:AZD8835; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors
keywords: Kinase; PI3Kα; PI3Kδ; PIK3CA mutation