Discovery and Characterization of Novel IKZF1/3 Glue Degraders against Multiple Hematological Cancer Cell Lines
Year: 2025
Type: article
Abstract: Objectives: Immunomodulatory drugs (IMiDs), functioning as molecular glue degraders, have been approved for treating various hematological malignancies; however, the inevitable acquired drug resistance resulting from their skeletal similarity and hematological toxicities poses significant obstacles to their clinical treatment. The study aimed to develop degraders with potent efficiency and low toxicity. Methods: Phenotypic profiling, elaborate structure-activity relationships (SAR), rational drug design and degradation profiles investigations, quantitative proteomics analysis and cell-based functional studies, and pharmacokinetic studies were conducted to develop more potent degraders. Results: . Furthermore, MGD-C9 exhibited significant synergistic effects with standard-of-care agents in various hematological malignancy cells. Conclusions: These results indicate that MGD-C9 could act as a highly effective CRBN ligand and is expected to become a candidate drug for the treatment of hematological malignancies.
Authors: Ting Wei, Pengli Wei, Yalei Wang, Yaqiu Mao, Jian Yan, Xiaotong Hu, Zhenze Qi, Xu Cai, Changkai Jia, Zhiyuan Zhao, Bingkun Li, Min Qiao, Yaxin Zou, Tingting Yang, Shiyang Sun, Xuesong Feng, Pengyun Li, Hongzhou Shang, Zhibing Zheng
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4413083398