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

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

Bernard Barlaam  1 , Sabina Cosulich  1 , Sébastien Degorce  1 , Martina Fitzek  1 , Stephen Green  1 , Urs Hancox  1 , Christine Lambert-van der Brempt  2 , Jean-Jacques Lohmann  2 , Mickaël Maudet  2 , Rémy Morgentin  2 , Aurélien Péru  2 , Patrick Plé  2 , Twana Saleh  2 , Lara Ward  1 , Nicolas Warin  2
Affiliations

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

Bernard Barlaam et al. Bioorg Med Chem Lett. .

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.

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