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DNA-dependent protein kinase (DNA-PK) inhibitors: structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain |
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| Authors: | Clapham Kate M Bardos Julia Finlay M Raymond V Golding Bernard T Griffen Edward J Griffin Roger J Hardcastle Ian R Menear Keith A Ting Attilla Turner Paul Young Gail L Cano Céline |
| Institution: | a Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom b KuDOS Pharmaceuticals Ltd, 410 Cambridge Science Park, Milton Rd., Cambridge CB4 0PE, United Kingdom c AstraZeneca Oncology iMed, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom |
| 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 (IC50 = 8 nM). |
| Keywords: | DNA repair DNA-PK Kinase inhibitors Anticancer drugs Structure-activity relationship studies |
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