Discovery of TQ-3959 as a Potent and Orally Bioavailable BTK PROTAC Degrader Incorporating a Novel Benzisoxazole-Based CRBN Ligand for the Treatment of B‑Cell Malignancies

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.