Ting Wei1,2,#, Pengli Wei2,3,#, Yalei Wang1,2, Yaqiu Mao2,3, Jian Yan2, Xiaotong Hu2, Zhenze Qi2, Xu Cai2, Changkai Jia2, Zhiyuan Zhao2, Bingkun Li2, Min Qiao2, Yaxin Zou2,3, Tingting Yang4, Shiyang Sun2, Xuesong Feng3, Pengyun Li2,*, Hongzhou Shang1,*, Zhibing Zheng2
Oncology Research, Vol.33, No.10, pp. 2981-3006, 2025, DOI:10.32604/or.2025.065123
- 26 September 2025
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: This study developed novel CRBN-binding moieties through methylene deletion in lenalidomide’s isoindole core. Lead… More >
Graphic Abstract