Kurt G Pike, Bernard Barlaam, Elaine Cadogan, Andrew Campbell, Yingxue Chen, Nicola Colclough, Nichola L Davies, Camila de-Almeida, Sebastien L Degorce, Myriam Didelot, Allan Dishington, Richard Ducray, Stephen T Durant, Lorraine A Hassall, Jane Holmes, Gareth D Hughes, Philip A MacFaul, Keith R Mulholland, Thomas M McGuire, Gilles Ouvry, Martin Pass, Graeme Robb, Natalie Stratton, Zhenhua Wang, Joanne Wilson, Baochang Zhai, Kang Zhao, Nidal Al-Huniti
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution)...
May 10, 2018: Journal of Medicinal Chemistry