Discovery of a dual-target CRBN-mediated degrader for IKZF1/3 and GSPT1 proteins.

The overexpression of IKZF1/3 (Ikaros and Aiolos) and GSPT1 (G1 to S phase transition protein 1) is closely linked to hematologic malignancies. Immunomodulatory drugs (IMiDs) like lenalidomide and pomalidomide degrade IKZF1/3 and are combined with other therapies to treat hematologic malignancies, including multiple myeloma and non-Hodgkin lymphoma. GSPT1 has emerged as a promising therapeutic target for blood cancers. Developing dual degraders targeting both IKZF1/3 and GSPT1 could synergistically enhance efficacy and improve treatment outcomes. This study identified a novel molecular glue degrader, DIX-01, which simultaneously targets and degrades IKZF1/3 and GSPT1 proteins. DIX-01 exhibited potent cytotoxicity in multiple cancer cell lines (22Rv1, MV4-11, HL-60, MOLM13), with IC values in the nanomolar range. Western blot analysis confirmed time-dependent and concentration-dependent degradation of IKZF1/3 and GSPT1. Proteomic analysis confirmed the targeted protein degradation by DIX-01, while transcriptomic sequencing further elucidated its modulation of signaling pathways. Molecular docking studies suggested that DIX-01 may form stable ternary complexes with CRBN-IKZF1 and CRBN-GSPT1, providing a structural basis for its dual-target degradation activity. Furthermore, DIX-01 significantly inhibited tumor growth in a zebrafish xenograft model transplanted with human acute myeloid leukemia cells (MV4-11), supporting its potential as a therapeutic agent for hematologic malignancies.