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

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• 作者：Bernard Barlaam^b ; ; Sabina Cosulich^b ; S&eacute ; bastien Degorce^b ; Martina Fitzek^b ; Stephen Green^b ; Urs Hancox^b ; Christine Lambert-van der Brempt^a ; Jean-Jacques Lohmann^a ; Micka&euml ; l Maudet^a ; R&eacute ; my Morgentin^a ; Aur&eacute ; lien P&eacute ; ru^a ; Patrick Pl&eacute ; ^a ; Twana Saleh^a ; Lara Ward^b ; Nicolas Warin^a
• 关键词：PI3Kβ/δ inhibitor ; Rational design ; PTEN-deficient tumours
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：26
• 期：9
• 页码：2318-2323
• 全文大小：2195 K

文摘

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.