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Discovery of a dual-target CRBN-mediated degrader for IKZF1/3 and GSPT1 proteins
Chunchao Tang1, Zhen Li2, Ruiqiang Lu3
1College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
Abstract:
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 IC50 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.
Insights
Researchers discovered DIX-01, a novel molecular glue that degrades Ikaros/Aiolos (IKZF1/3) and G1 to S phase transition protein 1 (GSPT1). This dual-target approach shows promise for treating hematologic malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Overexpression of Ikaros/Aiolos (IKZF1/3) and G1 to S phase transition protein 1 (GSPT1) is implicated in hematologic malignancies.
- Immunomodulatory drugs (IMiDs) targeting IKZF1/3 are used in treating multiple myeloma and non-Hodgkin lymphoma.
- GSPT1 is an emerging therapeutic target for blood cancers, suggesting dual-targeting strategies could improve outcomes.
Purpose of the Study:
- To identify and characterize a novel molecular glue degrader with dual-targeting capabilities against IKZF1/3 and GSPT1.
- To evaluate the efficacy and mechanism of action of the novel degrader in preclinical models of hematologic malignancies.
Main Methods:
- Identification of a novel molecular glue degrader, DIX-01.
- In vitro cytotoxicity assays across multiple cancer cell lines.
- Western blot and proteomic analysis to confirm protein degradation.
- Transcriptomic sequencing to elucidate pathway modulation.
- Molecular docking studies to predict binding interactions.
- In vivo efficacy studies using a zebrafish xenograft model.
Main Results:
- DIX-01 demonstrated potent, nanomolar cytotoxicity against various cancer cell lines.
- Confirmed time- and concentration-dependent degradation of IKZF1/3 and GSPT1 proteins.
- Proteomic and transcriptomic analyses validated targeted degradation and pathway modulation.
- Molecular docking suggested stable ternary complex formation with CRBN.
- DIX-01 significantly inhibited tumor growth in a zebrafish xenograft model.
Conclusions:
- DIX-01 is a novel molecular glue degrader that simultaneously targets IKZF1/3 and GSPT1.
- The dual-targeting mechanism shows significant preclinical efficacy against hematologic malignancies.
- DIX-01 represents a promising therapeutic candidate for blood cancers.
