2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2017 May 1;27(9):1949-1954. doi: 10.1016/j.bmcl.2017.03.027.
Bernard Barlaam 1,  Sabina Cosulich 2,  Sébastien Degorce 2,  Rebecca Ellston 3,  Martina Fitzek 3,  Stephen Green 3,  Urs Hancox 3,  Christine Lambert-van der Brempt 4,  Jean-Jacques Lohmann 4,  Mickaël Maudet 4,  Rémy Morgentin 4,  Patrick Plé 4,  Lara Ward 3,  Nicolas Warin 4
Affiliations

Affiliations

  • 1 IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom. Electronic address: bernard.barlaam2@astrazeneca.com.
  • 2 IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom.
  • 3 IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • 4 AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
PMID: 28347666 DOI: 10.1016/j.bmcl.2017.03.027
Abstract

Attempts to lock the active conformation of compound 4, a PI3Kβ/δ inhibitor (PI3Kβ cell IC50 0.015μM), 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 IC50 0.0011μM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC50 0.014μM 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.

Keywords

PI3Kβ/δ inhibitor; PTEN-deficient tumours; Rational design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101517
    PI3Kβ/δ Inhibitor