anti-HER2 GSPT1 degrader ORM-5029

A targeted protein degrader (TPD) composed of pertuzumab, an antibody directed against the tumor-associated antigen (TAA) human tyrosine kinase receptor epidermal growth factor receptor 2 (HER2; ErbB2; HER-2), conjugated, via a Val-Cit PABc cleavable linker, to SMol006, a membrane-permeable selective molecular glue degrader (MGD) of the translational termination factor GSPT1, with potential antineoplastic activity. Upon intravenous administration, anti-HER2 GSPT1 degrader ORM-5029 specifically targets and binds, with its pertuzumab moiety, to HER-2-expressing tumor cells. Upon internalization and cleavage, SMol006 specifically targets and binds to GSPT1, leading to GSPT1 degradation via the E3 ubiquitin ligase pathway. This disrupts oncogenic signaling, inhibits proliferation, and induces apoptosis in HER-2-driven tumors. The translation termination factor GSPT1, a G-loop degron-containing protein, plays a key role in protein translation and is dysregulated in various tumor cell types.