Ting Wei^1,2,#, Pengli Wei^2,3,#, Yalei Wang^1,2, Yaqiu Mao^2,3, Jian Yan², Xiaotong Hu², Zhenze Qi², Xu Cai², Changkai Jia², Zhiyuan Zhao², Bingkun Li², Min Qiao², Yaxin Zou^2,3, Tingting Yang⁴, Shiyang Sun², Xuesong Feng³, Pengyun Li^2,*, Hongzhou Shang^1,*, 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

GERHARD HAMILTON^*, MARIE-THERESE EGGERSTORFER, SANDRA STICKLER

Oncology Research, Vol.32, No.8, pp. 1257-1264, 2024, DOI:10.32604/or.2024.051653 - 17 July 2024

Abstract The Kirsten rat sarcoma virus—son of sevenless 1 (KRAS-SOS1) axis drives tumor growth preferentially in pancreatic, colon, and lung cancer. Now, KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS. However, the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%, lasting for a mean period of 8 months. One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras (PROTACs), which… More > Graphic Abstract