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

Bioorg Med Chem Lett. 2016 May 1;26(9):2318-23. doi: 10.1016/j.bmcl.2016.03.034. Epub 2016 Mar 11.

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.

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Mice
  • Morpholinos / chemistry*
  • Morpholinos / pharmacology*
  • PTEN Phosphohydrolase / genetics*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • Morpholinos
  • Phosphoinositide-3 Kinase Inhibitors
  • PTEN Phosphohydrolase
  • PTEN protein, human