atropisomeric PI3K beta-selective inhibitor
off-target tox. in higher species, discontinued
from rational design of known starting point
J. Med. Chem., Apr. 15, 2020
Gilead Sciences, Seattle, WA + Foster
“Compound (P)-14″ is a PI3K beta-isoform selective lipid kinase inhibitor. While the compound is potent and has excellent oral PK in higher species, significant irreversible toxicity was observed in a tox. study, and the chemical series was discontinued. It’s always great when organizations disclose tox. findings to educate the community. Interestingly the molecule has a significant barrier to rotation around the benzimidazole ring and can be isolated as a stable atropisomer.