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  • In light of the overall loss of activity and selectivity


    In light of the overall loss of activity and selectivity observed with this series of arylchromenone-4-ones bearing small -alkoxy substituents, we were pleased to identify a potent and relatively selective inhibitor , exhibiting IC values of 0.008μM and 0.07μM for DNA-PK and PI3Kα, respectively. The fact that is approximately ninefold selective for DNA-PK versus PI3Kα and fourfold more potent than the parent 8-dibenzothiophenyl chromen-4-one , suggests that the cyclopropylmethoxy group of might be making productive interactions with a Efaproxiral Sodium region of the ATP-binding domain of DNA-PK. It is notable that compared to , the -butyl analogue is ca. 20-fold less potent against DNA-PK but only ca. twofold less potent against PI3Kα. In summary, we have identified a novel series of -alkoxyphenyl chromen-4-ones that exhibit a range of potencies against DNA-PK. These compounds represent the first exemplified chromenone-based DNA-PK inhibitors that lack an aryl substituent directly attached at the C-2 position of the phenyl ring. With the exception of the cyclopropylmethoxy derivative , the most potent and a modestly selective inhibitor, achieving selectivity for DNA-PK over PI3Kα has proven challenging. Overall, this study has further elucidated our understanding of SARs around a putative hydrophobic region of the ATP-binding site, indicating a limited steric tolerance and hydrophobic complementarily. Further studies are currently underway to elucidate the binding mode of this class of chromen-4-one based DNA-PK inhibitors. Acknowledgements