Discovery of <b>TQ-3959</b> as a Potent and Orally Bioavailable BTK PROTAC Degrader Incorporating a Novel Benzisoxazole-Based CRBN Ligand for the Treatment of B-Cell Malignancies
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
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 (DC 50 = 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.