anti-CD33 GSPT1 degrader BMS-986497

A targeted protein degrader (TPD) composed of OR000283, an antibody directed against the tumor-associated antigen (TAA) cluster of differentiation 33 (CD33), conjugated, via a cleavable beta-glucuronide 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-CD33 GSPT1 degrader BMS-986497 specifically targets and binds, with its antibody moiety, to CD33-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 CD33-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. CD33, a cell surface antigen expressed on normal non-pluripotent hematopoietic stem cells, is overexpressed on myeloid leukemia cells.