9. The Shionogi BACE1 aspartyl protease inhibitor, atabecestat (JNJ-54861911) is an oral, brain-penetrant compound that was advanced into the EARLY Ph. IIb/III clinical trial for treatment of preclinical Alzheimer’s disease (AD) patients. The starting point was identified from a phenotypic HTS, and was the first thiazine-based BACE1 disclosed in the patent literature. The Shionogi team discloses that the trial was discontinued due to liver enzyme elevation, and subsequent analysis showed that the treatment group actually had dose-related cognitive worsening, in agreement with other company’s findings. The Shionogi team shares a lot of helpful development details including their studies to de-risk an early 500 nM in vitro hERG signal.