Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor
Barbara Czako and colleaugues, IACS (Institute for Applied Cancer Science), University of Texas MD Anderson Cancer Center, Houston
Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) has been an interesting target for small molecule inhibitors for the treatment of cancer. In recent years inhibitors have appeared and these, as ever, have sparks a flurry of drug discovery program. This full paper, from the IACS, takes us on the journey of SAR exploration, series characterisations, structure-based drug design which led to a ‘scaffold-hop’ and optimisation of PK and hERG binding. Interesting the final compound has additional chirality from atropisomerism (it seems there are a few of these at the moment).