AZD4625 is a Potent and Selective Inhibitor of KRASG12C
Atanu Chakraborty, Lyndsey Hanson, David M. Robinson, Hilary Lewis, Sue Bickerton, Michael Davies, Radosław Polański, Rebecca Whiteley, Alex Koers, James Atkinson, Tamara Baker, Iván del Barco Barrantes, Giovanni Ciotta, Jason G. Kettle, Łukasz Magiera, Carla P. Martins, Alison Peter, Eleanor M. Wigmore, Zoe Underwood, Sabina Cosulich, Michael Niedbala, Sarah J. Ross
Abstract
AZD4625 is a potent, selective, and orally bioavailable inhibitor of oncogenic KRASG12C as demonstrated in cellular assays and in vivo in preclinical cell line-derived and patient-derived xenograft models. In vitro and cellular assays have shown selective binding and inhibition of the KRASG12C mutant isoform, which carries a glycine to cysteine mutation at residue 12, with no binding and inhibition of wild-type RAS or isoforms carrying non-KRASG12C mutations. The pharmacology of AZD4625 shows that it has the potential to provide therapeutic benefit to patients with KRASG12C mutant cancer as either a monotherapy treatment or in combination with other targeted drug agents.