W Cameron Black, Abbas Abdoli, Xiuli An, Anick Auger, Patrick Beaulieu, Michel Bernatchez, Cathy Caron, Amandine Chefson, Sheldon Crane, Mohamed Diallo, Stéphane Dorich, Lee D Fader, Gino B Ferraro, Sara Fournier, Qi Gao, Yelena Ginzburg, Martine Hamel, Yongshuai Han, Paul Jones, Stéphanie Lanoix, Cyrus M Lacbay, Marie-Eve Leclaire, Maayan Levy, Yael Mamane, Amina Mulani, Robert Papp, Charles Pellerin, Audrey Picard, Alexander Skeldon, Kathryn Skorey, Rino Stocco, Miguel St-Onge, Jean-François Truchon, Vouy Linh Truong, Michal Zimmermann, Michael Zinda, Anne Roulston
ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia...
February 1, 2024: Journal of Medicinal Chemistry