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. Epub 2015 Oct 9.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Dogs
  • Humans
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Molecular Docking Simulation
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / pharmacology*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Piperidines / chemical synthesis
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Xenograft Model Antitumor Assays

Substances

  • AZD8835
  • Antineoplastic Agents
  • Oxadiazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperidines
  • Protein Kinase Inhibitors