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

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

  • Bioorg Chem. 2026 Feb:169:109367. doi: 10.1016/j.bioorg.2025.109367.
Chunchao Tang 1,  Zhen Li 2,  Ruiqiang Lu 3,  Guangliang Yu 4,  Yuchao Gu 5,  Xiaojun Yao 6
Affiliations

Affiliations

  • 1 College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
  • 2 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 3 Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China.
  • 4 Suzhou Degen Bio-medical Co., Ltd, No.1 Hua yun Road, SIP, Suzhou 215000, China.
  • 5 Qingdao Shark VNARs Development Technology Innovation Center, College of Biological Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China. Electronic address: [email protected].
  • 6 Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China. Electronic address: [email protected].
PMID: 41411691 DOI: 10.1016/j.bioorg.2025.109367
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.

Keywords

Acute myelogenous leukemia; Dual-target; GSPT1; IKZF1/3; Molecular dynamics simulation; Molecular glue.

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