CRBN-KO Can Still Show Drug Activity? This BTK Degrader Is Seriously Impressive

In previous articles, we introduced BTK-related BaF3-BTK-mutation kinase cell models and the TMD8-BTK-endoMut endogenous mutation cell model (see related official account links at the end). Whether for BTK kinase inhibitors or BTK degraders, these models are ideal for in vitro and in vivo research and screening. To date, six BTK inhibitors have been approved globally, including Ibrutinib, Acalabrutinib, Zanubrutinib, Orelabrutinib, Tirabrutinib, and Pirtobrutinib. Among them, Zanubrutinib surpassed USD 1.3 billion in sales in 2023, becoming a blockbuster domestic drug. Pirtobrutinib, as a third-generation non-covalent inhibitor, addresses resistance caused by the C481S mutation. In addition, Hutchmed’s HMPL-760, also a third-generation non-covalent inhibitor, is currently in clinical trials for diffuse large B-cell lymphoma and has demonstrated potential in overcoming resistance.

BTK degraders, such as PROTACs, represent a new generation of targeted therapies. Compared with traditional kinase inhibitors, they show significant advantages and broad application prospects in clinical research.

Broad-Spectrum Activity Against Resistance Mutations

Traditional kinase inhibitors, such as Ibrutinib, rely on covalent binding to the Cys481 residue of BTK. Mutations such as C481S lead to loss of binding. Degraders directly eliminate the BTK protein via the ubiquitin–proteasome system and remain effective against resistance mutations including C481S, T474I, and L528W. For example, in our TMD8-BTK-endoMut model, NX-5948 showed significantly superior activity against cells harboring C481X, T474I, L528W, and other mutations compared with traditional inhibitors.

Comprehensive Functional Blockade

Degraders not only inhibit kinase activity but also eliminate non-enzymatic functions of BTK, such as its scaffolding role. In systemic lupus erythematosus (SLE) mouse models, L18I degraded BTK protein and simultaneously inhibited B-cell BCR signaling and monocyte/macrophage TLR signaling pathways, significantly reducing anti-dsDNA antibody levels and inflammatory cytokine secretion. In contrast, Ibrutinib only partially inhibited BCR signaling. This dual inhibitory mechanism was also evident in a diffuse alveolar hemorrhage (DAH) model, where L18I reduced the incidence of pulmonary hemorrhage by 70 percent, outperforming Ibrutinib’s 45 percent.

Improved Selectivity and Safety

Through bifunctional design that simultaneously binds BTK and an E3 ligase, degraders achieve higher target specificity. For example, TQB3019 shows 99.7 percent selectivity for BTK degradation and does not affect CRBN substrates such as GSPT1 and IKZF1/3, avoiding common off-target toxicities seen with traditional inhibitors, such as atrial fibrillation and hypertension. In CLL patients, the incidence of thrombocytopenia with NX-5948 was only 23.5 percent, with grade 3 or higher at 2.9 percent, significantly lower than the 51.3 percent observed with Ibrutinib.

More Durable Efficacy

Degraders achieve deep suppression by eliminating BTK protein. In relapsed or refractory CLL patients, Nurix’s NX-5948 achieved an objective response rate (ORR) of 76.7 percent, with 68 percent of patients maintaining responses for more than 12 months. In contrast, traditional inhibitors typically show ORRs below 30 percent in resistant patients. BeiGene’s BGB-16673 achieved an ORR of 94 percent in a phase I trial at the 200 mg dose, with two cases of complete response (CR), and a median duration of response exceeding 8 months.

Both NX-5948 and BGB-16673 are CRBN-based degraders. Interestingly, in our TMD8-CRBN-KO cell model, the sensitivity of NX-5948 decreased by 100-fold compared with TMD8 wild-type cells, demonstrating that its degradation activity is CRBN-dependent. In contrast, BGB-16673 showed no change in sensitivity in the CRBN-KO model and maintained efficacy comparable to TMD8 wild-type cells. This further supports the uniqueness and potential of BeiGene’s CDAC platform technology, which can overcome E3 ligase-related resistance. The results are shown in the table below:

The global BTK degrader market is expected to exceed USD 5 billion by 2030. Drugs that have entered the clinical stage include:

NX-5948 (Nurix): Phase Ib expansion study showed an ORR of 76.7 percent in previously treated CLL patients, with an NDA submission expected in 2025.

TQB3019 (Chia Tai Tianqing): Phase I trial demonstrated good safety, with plans to initiate a phase III study for SLE in 2026.

BGB-16673 (BeiGene): Phase I trial showed a CR rate of 4 percent, with a head-to-head trial versus Zanubrutinib planned for 2025.

Through the paradigm shift of “degradation replacing inhibition,” BTK degraders are reshaping the treatment landscape for hematologic malignancies and autoimmune diseases. Their advantages extend beyond overcoming resistance and improving safety, offering a new framework for the development of first-in-class therapies.

Product and Service List: BTK Mutant Cell Lines and In Vitro Validation Covering 20+ high-frequency clinical mutations including C481S and T474I; support for single-point and compound mutation customization