Identification of potent and orally bioavailable GSPT1 molecular glue degraders

Abstract

G1 to S phase transition 1 (GSPT1) is involved in multiple biological processes and is significantly overexpressed in various cancer tissues and cells. Degradation of GSPT1 protein proves to be a potential therapeutic option through the technology of molecular glue, however, no molecules have been approved for clinical use. Here, we report our efforts on Structure-Activity Relationship studies around an innovative tricyclic-containing derivatives as potent and orally bioavailable GSPT1 degraders. An in vivo xenograft model study showed that one of the synthesized compounds (26) effectively suppressed NCI-N87 tumor growth, suggesting a direction in the development of novel GSPT1 degraders.