title: Discovery of a series of 8-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-2-morpholino-4-oxo-chromene-6-carboxamides as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours.
abstract: We report the discovery and optimisation of a series of 8-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-2-morpholino-4-oxo-chromene-6-carboxamides, leading to compound 16 as a potent and selective PI3Kβ/δ inhibitor: PI3Kβ cell IC50 0.012 μM (in PTEN null MDA-MB-468 cell) and PI3Kδ cell IC50 0.047 μM (in Jeko-1 B-cell), with good pharmacokinetics and physical properties. In vivo, 16 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-deficient PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Compound 16 was selected as a preclinical candidate for the treatment of PTEN-deficient tumours.
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Degorce
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Martina
authors.initials: M
authors.lastname: Fitzek
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.affiliation: AstraZeneca Pharmaceuticals, 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: 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: Jean-Jacques
authors.initials: JJ
authors.lastname: Lohmann
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Maudet
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: Aurélien
authors.initials: A
authors.lastname: Péru
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Plé
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 Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Lara
authors.initials: L
authors.lastname: Ward
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Warin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D060172:Morpholinos / Q000737:chemistry* / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D060172:Morpholinos; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PI3Kβ/δ inhibitor; PTEN-deficient tumours; Rational design