PROTAC BTK degrader(Southern Medical University)

Selective inhibition of phosphodiesterase (PDE) 4B favorably suppresses the synthesis of inflammatory cytokines and subsequently arrest the development of atopic dermatitis via modulating the intracellular cAMP levels. Considering the side effects of corticosteroids, selective PDE4 inhibition could constitute an effective alternative therapy for the treatment of atopic dermatitis (AD). In this study, a series of novel catechol based compounds bearing pyrimidine as the core have been synthesized and screened for the PDE4 inhibitory properties. The PDE4 selectivity of the active compounds over other PDEs has been investigated. Compound 23 bearing pyrimidine core functionalized with catechol, pyridine and trifluoromethyl groups can effectively inhibit the PDE4B with IC₅₀ value in nanomolar range (IC₅₀ = 15 ± 0.4 nM). Compound 23 exhibited seven fold higher selectivity towards PDE4B over PDE4D. Molecular Docking study confirmed its stronger affinity towards catalytic domain of PDE4B. In-vivo analysis confirmed that compound 23 effectively alleviated the symptoms of atopic dermatitis in DNCB-treated Balb/c mice by suppressing the synthesis of inflammatory mediators such as TNF-α, and Ig-E. Taken together, this study suggested that compound 23 could be an effective PDE4 inhibitor for the potential treatment of AD.

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.