title: Discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-one as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours.
abstract: Attempts to lock the active conformation of compound 4, a PI3Kβ/δ inhibitor (PI3Kβ cell IC500.015μM), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kβ/δ inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kβ cell IC500.0011μM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC500.014μM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kβ/δ preclinical candidates.
authors.affiliation: IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom. Electronic address: bernard.barlaam2@astrazeneca.com.
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.affiliation: IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.affiliation: IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Degorce
authors.affiliation: IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ellston
authors.affiliation: IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Martina
authors.initials: M
authors.lastname: Fitzek
authors.affiliation: IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.affiliation: IMED Oncology, AstraZeneca, 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: Patrick
authors.initials: P
authors.lastname: Plé
authors.affiliation: IMED Oncology, AstraZeneca, 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; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001578:Benzopyrans / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004285:Dogs; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D060172:Morpholinos / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D060172:Morpholinos; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PI3Kβ/δ inhibitor; PTEN-deficient tumours; Rational design