DNA-dependent protein kinase (DNA-PK) inhibitors: Structure–activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain

Bioorganic & Medicinal Chemistry Letters
2011.0

Abstract

Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC(50)=8 nM).

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