Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500)
W. Cameron Black, Abbas Abdoli, Xiuli An, Anick Auger, Patrick Beaulieu, Michel Bernatchez, C. Caron, Amandine Chefson, Sheldon N. Crane, Mohamed Lamine Diallo, Stéphane Dorich, Lee D. Fader, Gino B. Ferraro, Sara Fournier, Qi Gao, Yelena Ginzburg, Martine Hamel, Yongshuai Han, Paul D. Jones, Stéphanie Lanoix, Cyrus M. Lacbay, Marie-Ève Leclaire, Maayan Levy, Yaël 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
Abstract
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. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.