Discovery of TQ-3959 as a Potent andOrally Bioavailable BTK PROTAC Degrader Incorporating a Novel Benzisoxazole-BasedCRBN Ligand for the Treatment of B-Cell Malignancies

作者：Jing Ren, Yongkang Huang, Ji-Nan Wang, Sheng Xu, Lei Wang, Qingran Yan, Xiaoping Zhang, Lilong Wang, Qinglin Wang, Xiaojin Wang, Yingpeng Zhang, Hengqiao Shen, Lijuan Zhu, Shuwen Xue, Mincheng Zhang, Hongjiang Xu, Baomin Liu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00956 · 被引用次数：6 · 研究领域：Protein Degradation and Inhibitors、Chronic Lymphocytic Leukemia Research、CAR-T cell therapy research

Abstract BTK is a critical nonreceptor tyrosine kinase involved in BCR signaling and represents a validated target for treating B-cell malignancies and autoimmune diseases. Although several BTK inhibitors have been approved, their clinical application is limited by drug resistance and off-target effects. PROTACs offer a promising alternative strategy by degrading BTK through the ubiquitin–proteasome system. Herein, we report the design and optimization of a new class of BTK PROTACs incorporating a novel benzisoxazole-based CRBN ligand. Compound 17 (TQ-3959) exhibited exceptional degradation potency (DC50 = 0.4 nM) and oral bioavailability (F = 58.0%) in mice. Importantly, TQ-3959 exhibited potent antiproliferative activity in vitro against multiple lymphoma cell lines and effectively inhibited tumor growth in vivo, achieving nearly complete regression in a TMD-8 xenograft mouse model. Our data demonstrate that TQ-3959 is a promising BTK PROTAC degrader for extensive evaluation as a new therapy for the treatment of lymphoma.