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
J. Med. Chem. 2021, 64, 20, 15141–15169
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).