Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500)

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.