molecules of the month

Context. T-690 (Takeda) is an oral GCS inhibitor that is brain-penetrant, non-basic, and non-competitive with UDP-glucose. We recently highlighted a glucosylceramide synthase (GCS, aka CGT) inhibitor in Ph. III (Sanofi’s venglustat). GCS inhibition may reduce glycosphingolipid levels downstream of its product, glucosylceramide (GlcCer). GCS inhibitors have been clinically explored in diseases where accumulation of glycosphingolipids may contribute to pathology, including GBA-mutant Parkinson’s disease and various rare genetic diseases. The Takeda molecule has a distinct structure from previously reported GCS inhibitors (Eliglustat, EXEL-0346, venglustat and BZ1). Existing GCS inhibitors such as miglustat and eliglustat do not treat the neuropathic symptoms of diseases like Gaucher’s Disease (GD), but the Takeda team suggests that a brain-penetrant GCS inhibitor (like venglustat or Merck’s BZ1)…