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

  • Bioorg Med Chem Lett. 2015 Nov 15;25(22):5155-62. doi: 10.1016/j.bmcl.2015.10.002.
Bernard Barlaam  1 ,  Sabina Cosulich  2 ,  Bénédicte Delouvrié  3 ,  Rebecca Ellston  2 ,  Martina Fitzek  2 ,  Hervé Germain  3 ,  Stephen Green  2 ,  Urs Hancox  2 ,  Craig S Harris  3 ,  Kevin Hudson  2 ,  Christine Lambert-van der Brempt  3 ,  Honorine Lebraud  3 ,  Françoise Magnien  3 ,  Maryannick Lamorlette  3 ,  Antoine Le Griffon  3 ,  Rémy Morgentin  3 ,  Gilles Ouvry  3 ,  Ken Page  2 ,  Georges Pasquet  3 ,  Urszula Polanska  2 ,  Linette Ruston  2 ,  Twana Saleh  3 ,  Michel Vautier  3 ,  Lara Ward  2
Affiliations
  • 1. AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Electronic address: [email protected].
  • 2. AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • 3. AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
PMID: 26475521 DOI: 10.1016/j.bmcl.2015.10.002
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.

Keywords
Kinase; PI3Kα; PI3Kδ; PIK3CA mutation.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12869
    AZD-8835
    98.38%, PI3Kα/δ Inhibitor
    target: PI3K
    Research Areas: Cancer